Methods to treat lymphoplasmacytic lymphoma

ABSTRACT

The present invention provides compounds of any one of Formulae (A), (I-11), (II), and (V) (e.g., compounds of Formula (A-1)-(A-18)), and methods for treating Waldenström&#39;s macroglobulinemia (WM) and other B cell neoplams in a subject using the compounds. The methods comprise administering to a subject in need thereof an effective amount of the compounds. Also provided are methods to treat B cell neoplasms using the compounds in combination with inhibitors of Bruton&#39;s tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.

The present application claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent applications, U.S. Ser. No. 62/036,934, filed Aug. 13, 2014 and U.S. Ser. No. 61/915,684, filed Dec. 13, 2013, the entire contents of which are incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with U.S. Government support under grants 5R01CA130876-05, 5P50CA090578-10, 5R01CA136851-04, 2R01CA136851-05, and 1R01CA172592-01A1 awarded by the National Cancer Institute. The U.S. Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

Waldenström's macroglobulinemia (WM) is a distinct clinicopathological entity resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells which secrete a monoclonal IgM protein. This condition is considered to correspond to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification system. WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually. There is a 2- to 3-fold risk increase of developing WM in people with a personal history of autoimmune diseases with autoantibodies and particularly elevated risks associated with hepatitis, human immunodeficiency virus, and rickettsiosis (Arch. Intern. Med., 2008, 168(17), 1903-9). There is no single accepted treatment for WM, and there can be a marked variation in clinical outcome. Objective response rates are high (>80%) but complete response rates are low (0-15%) (Clin. Adv. Hematol. Oncol., 2009, 7(10), 677-81, 687-90). Thus, there is a need for effective treatment of WM.

SUMMARY OF THE INVENTION

The present invention is based, at least in part, on the discovery of compounds of the Formula (A):

or a pharmaceutically acceptable salt thereof, wherein Q, U, R^(A), R^(B), R^(X), k, and l are defined herein, for the treatment of Waldenström's macroglobulinemia. The activity of these compounds was established by in vitro screening against several kinases (e.g., BTK, HCK, TAK1, HPK1).

In certain embodiments, compounds of Formula (A) are of formula:

and pharmaceutically acceptable salts thereof.

Another aspect of the invention relates to the compound of Formula (I-11):

and pharmaceutically acceptable salts thereof.

The present invention also provides compounds of Formula (II) or (V):

and pharmaceutically acceptable salts thereof, wherein Ring A′, Ring C′, Cy, X′, Y′, Z′, Q′, U′, R^(A)′, R^(B)′, R^(D)′, R^(X)′, k′, l′, and m′ are as defined herein.

The present invention is also based, at least in part, on the discovery that Waldenström's macroglobulinemia may be treated by administration of a compound of the invention to a subject in need thereof. The activity of these compounds was established by in vitro screening against several kinases (e.g., BTK, HCK, TAK1, HPK1) that are involved in the regulation of aberrant cell growth, as well as cell-based screening against several cell lines (e.g., BCWM.1, MWCL-1) that are disease state models of Waldenström's macroglobulinemia (Ditzel et al. Exp Hematol. 2007 September;35(9):1366-75; Hodge et al. Blood. 2011 May 12;117(19)).

The methods of treatment utilizing a compound of the invention also apply to B cell neoplasms of the group consisting of Hodgkin's lymphomas and most non-Hodgkin's lymphomas, such as diffuse large B cell lymphoma, Follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with chronic lymphocytic leukemia), mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), Intravascular large B-cell lymphoma, Primary effusion lymphoma, and Lymphomatoid granulomatosis.

The present invention is also based, at least in part, on pharmaceutical compositions comprising a compound of the invention (e.g., a compound of Formula (A), (I-11), (II), or (V) (e.g., compounds of Formula (A-1)-(A-18))) and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition may be useful for modulating the activity of a kinase in vitro or in a subject in need thereof, and/or for treating and/or preventing in a subject in need thereof a condition associated with aberrant activity of a kinase (e.g., a proliferative disease). In certain embodiments, the pharmaceutical composition may be useful for treatment of Waldenström's macroglobulinemia in a subject in need thereof.

The present invention also provides kits comprising a container with a compound of the invention (e.g., a compound of Formula (A), (I-11), (II), or (V) (e.g., compounds of Formula (A-1)-(A-18))), or a pharmaceutical composition thereof. The kits may include a single dose or multiple doses of a compound described herein or a pharmaceutical composition thereof. The kits may be useful for modulating the activity of a kinase in a subject in need thereof. The kits may also be useful for treating and/or preventing in a subject in need thereof a condition associated with aberrant activity of a kinase. In certain embodiments, the kits further include instructions for using the kit (e.g., for administering a compound described herein, or a pharmaceutical composition thereof).

The details of particular embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Figures, the Examples, and the Claims.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^(rd) Edition, Cambridge University Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of ¹⁹F with ¹⁸F, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

When a range of values is listed, it is intended to encompass each value and subrange within the range. For example “C₁₋₆ alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆, C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The term “aliphatic,” as used herein, refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” as used herein, refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl (C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C₁₋₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g., —CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C₁₋₁₀ alkyl (such as substituted C₁₋₆ alkyl, e.g., CF₃, Bn).

As used herein, “haloalkyl” is a substituted alkyl group as defined herein wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In certain embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C₁₋₈ haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C₁₋₆ haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C₁₋₄ haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C₁₋₃ haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C₁₋₂ haloalkyl”). In certain embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group. In certain embodiments, all of the haloalkyl hydrogen atoms are replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include —CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl, and the like.

As used herein, “heteroalkyl” refers to an alkyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC₁₋₁₀ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC₁₋₉ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC₁₋₈ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC₁₋₇ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC₁₋₆ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC ₁₋₅ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and for 2 heteroatoms within the parent chain (“heteroC₁₋₄ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC₁₋₃ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC₁₋₂ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC₁ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₆ alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC₁₋₁₀ alkyl.

As used herein, “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂₋₉ alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂₋₈ alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additional examples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenyl group is a substituted C₂₋₁₀ alkenyl. In an alkenyl group, a C═C double bond for which the stereochemistry is not specified (e.g., CH═CHCH₃ or

may be an (E)- or (Z)-double bond

As used herein, “heteroalkenyl” refers to an alkenyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC₂₋₁₀ alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC₂₋₉ alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈ alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC₂₋₇ alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆ alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₅ alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and for 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC₂₋₃ alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₆ alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC₂₋₁₀ alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC₂₋₁₀ alkenyl.

As used herein, “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C₂₋₁₀ alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and the like. Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynyl group is a substituted C₂₋₁₀ alkynyl.

As used herein, “heteroalkynyl” refers to an alkynyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC₂₋₁₀ alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC₂₋₉ alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈ alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC₂₋₇ alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆ alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₅ alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and for 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC₂₋₃ alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₆ alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC₂₋₁₀ alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC₂₋₁₀ alkynyl.

As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a nonaromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C₃₋₁₄ carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C₃₋₁₀ carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C₃₋₈ carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C₃₋₇ carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C₄₋₆ carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C₅₋₆ carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C₃₋₈ carbocyclyl groups include, without limitation, the aforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclyl groups include, without limitation, the aforementioned C₃₋₈ carbocyclyl groups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C₃₋₁₄ carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₄ carbocyclyl. In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C₃₋₁₄ cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C₃₋₁₀ cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C₃₋₈ cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In certain embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C₄₋₆ cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆ cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groups include cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆ cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups as well as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈ cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C₃₋₁₄ cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C₃₋₁₄ cycloalkyl.

As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

In certain embodiments, a heterocyclyl group is a 5-10 membered nonaromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5-8 membered nonaromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5-6 membered nonaromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In certain embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). In certain embodiments, an aryl group has 6 ring carbon atoms (“C₆ aryl”; e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In certain embodiments, an aryl group has 14 ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C₆₋₁₄ aryl. In certain embodiments, the aryl group is a substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of “alkyl” and refers to an alkyl group, as defined herein, substituted by an aryl group, as defined herein, wherein the point of attachment is on the alkyl moiety.

As used herein, “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

In certain embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In certain embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In certain embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein, wherein the point of attachment is on the alkyl moiety.

As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.

As used herein, the term “saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.

Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

As understood from the above, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are, in certain embodiments, optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂, —N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —NOR^(cc))R^(bb), —SH, —SR^(aa), —SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa), —OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂, —NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂, —NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa), —NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa), —S(═O)R^(aa), —OS (═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)S R^(aa), —SC(═S)S R^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B (R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group ═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa), ═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(aa) groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(bb) groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(cc) groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂, —N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee), —C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee), —C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(V)₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd) substituents can be joined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆ alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(ff) groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, −NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃ ⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆ alkyl)₃—C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R^(gg) substituents can be joined to form ═O or ═S; wherein X⁻ is a counterion.

As used herein, the term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, —OH, —OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl (e.g., alkyl, aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ heteroalkyl, C₂₋₁₀ heteroalkenyl, C₂₋₁₀ heteroalkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa) R^(bb), R^(cc) and R^(dd) are as described herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g., —C(═O)R^(aa)) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g., —C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBDTmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′-and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g., —S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3dibenzyl-1,3,5-triazacyclohexan-2-one, 1substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as described herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein by reference.

Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7aoctahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

In certain embodiments, the substituent present on an sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as described herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein by reference.

As used herein, a “leaving group”, or “LG”, is a term understood in the art to refer to a molecular fragment that departs with a pair of electrons upon heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halides (such as chloride, bromide, or iodide), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, haloformates, —NO₂, trialkylammonium, and aryliodonium salts. In certain embodiments, the leaving group is a sulfonic acid ester. In certain embodiments, the sulfonic acid ester comprises the formula —OSO₂R^(LG1) wherein R^(LG1) is selected from the group consisting alkyl optionally, alkenyl optionally substituted, heteroalkyl optionally substituted, aryl optionally substituted, heteroaryl optionally substituted, arylalkyl optionally substituted, and heterarylalkyl optionally substituted. In certain embodiments, R^(LG1) is substituted or unsubstituted C₁-C₆ alkyl. In certain embodiments, R^(LG1) is methyl. In certain embodiments, R^(LG1) is —CF₃. In certain embodiments, R^(LG1) is substituted or unsubstituted aryl. In certain embodiments, R^(LG1) is substituted or unsubstituted phenyl. In certain embodiments R^(LG1) is:

In some cases, the leaving group is toluenesulfonate (tosylate, Ts), methanesulfonate (mesylate, Ms), p-bromobenzenesulfonyl (brosylate, Bs), or trifluoromethanesulfonate (triflate, Tf). In some cases, the leaving group is a brosylate (p-bromobenzenesulfonyl). In some cases, the leaving group is a nosylate (2-nitrobenzenesulfonyl). In certain embodiments, the leaving group is a sulfonate-containing group. In certain embodiments, the leaving group is a tosylate group. The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.

These and other exemplary substituents are described in more detail in the Detailed Description, Figures, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Other Definitions

The following definitions are more general terms used throughout the present application.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N⁺(C₁₋₄ alkyl)₄ ⁻ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. Compounds of the invention may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R·x H₂O, wherein R is the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R·0.5 H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R.2 H₂O) and hexahydrates (R.6 H₂O)).

The term “tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

The term “polymorphs” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly the C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters of the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows isobolograms demonstrating the synergy between compound (A-17) and a BTK inhibitor. Points below the 1 to 1 line connecting the X and Y axes are ‘synergistic’, points near the line are ‘additive’, and points above it are antagonistic.

DETAILED DESCRIPTION OF THE INVENTION

In an effort to identify novel treatments for Waldenström's macroglobulinemia, in vitro screens were carried out against several kinases (e.g., BTK, HCK, TAK1, HPK1). These kinases are involved in the regulation of aberrant cell growth associated with this condition. Cell-based screening was also carried out in several disease state model lines of Waldenström's macroglobulinemia (e.g., BCWM.1, MWCL-1). Based on these screening efforts and subsequent lead optimization, compounds of any one of Formulae (A), (I-11), (II), and (V) (e.g., compounds of Formula (A-1)-(A-18)) were identified.

In one aspect, the present invention provides compounds of Formula (A):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof; wherein:

each instance of R^(A) is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, —OR^(A1), —N(R^(A1))₂, —CN, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —NO₂, —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1), —NR^(A1)S(═O)₂R^(A1), —S(═O)₂R^(A1), or —S(═O)₂N(R^(A1))₂;

each instance of R^(B) is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A1))₂, —CN, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —NO₂, —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1), —NR^(A1)S(═O)₂R^(A1), —S(═O)₂R^(A1), or —S(═O)₂N(R^(A1))₂;

each instance of R^(A1) is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R^(A1) groups are joined to form an optionally substituted heterocyclic ring;

one instance of A that is included in Ring B is CR^(Y);

the other instance of A that is included in Ring B is CR^(Y) or N;

each instance of R^(Y) is independently H, halogen, or substituted or unsubstituted C₁₋₆ alkyl;

each instance of R^(X) is independently selected from the group consisting of R^(D), optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and —N(R^(A1))(R^(Xa));

each instance of R^(Xa) is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —S(═O)R^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), —S(═O)₂N(R^(A1))₂, —N(R^(A1))₂, and a nitrogen protecting group;

k is 0, 1, 2, 3, or 4;

l is 1, 2, 3, 4, or 5;

Q and U are taken together to be NR^(A)(C═O)— or —(C═O)NR^(A)—; and

R^(D) is an electrophilic moiety as described herein.

In certain embodiments, the present invention provides compounds from the group consisting of:

and pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides methods for treating Waldenström's macroglobulinemia (WM) in a subject using compounds of the invention. The methods comprise administering to a subject in need thereof an effective amount of a compound of the invention. Also provided are methods to treat other B cell neoplasms using compounds of the invention in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase. In certain embodiments, one or more compounds of the invention are used in combination with an inhibitor of the phosphoinositide 3-kinase delta isoform (PI3Kδ). In certain embodiments, combinations of 2, 3, 4, 5, 6,7, 8, 9, 10, or more of the agents described herein are used for treating WM. In certain embodiments, the agents described herein are used in combination with kinase inhibitors such as inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), and/or phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.

Waldenstrom's macroglobulinemia (WM) is a distinct clinicopathological entity resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells which secrete a monoclonal IgM protein. This condition is considered to correspond to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification system. Genetic factors play an important role in the pathogenesis of WM, with 25% of patients demonstrating a family history. IgM monoclonal gammopathy of unknown significance (MGUS) often precedes the development of WM.

As used herein, a B cell neoplasm includes both Hodgkin's lymphoma and non-Hodgkin's lymphomas. Classical Hodgkin's lymphoma (HL) includes various subtypes such as Nodular sclerosing HL, Mixed-cellularity subtype, Lymphocyte-rich or Lymphocytic predominance and Lymphocyte depleted. Examples of B cell non-Hodgkin's lymphomas include, but are not limited to, Waldenström's macroglobulinemia, diffuse large B cell lymphoma, follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with chronic lymphocytic leukemia), mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), intravascular large B-cell lymphoma, primary effusion lymphoma, and lymphomatoid granulomatosis.

In certain embodiments, the subject is administered a compound of Formula (A):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof; wherein:

each instance of R^(A) is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, —OR^(A1), —N(R^(A1))₂, —CN, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —NO₂, —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1), —NR^(A1)S(═O)₂R^(A1), —S(═O)₂R^(A1), or —S(═O)₂N(R^(A1))₂;

each instance of R^(B) is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A1))₂, —CN, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —NO₂, —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1), —NR^(A1)S(═O)₂R^(A1), —S(═O)₂R^(A1), or —S(═O)₂N(R^(A1))₂;

each instance of R^(A1) is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R^(A1) groups are joined to form an optionally substituted heterocyclic ring;

each instance of R^(X) is independently selected from the group consisting of R^(D), optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and —N(R^(A1))(R^(Xa));

each instance of R^(Xa) is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —S(═O)R^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), —S(═O)₂N(R^(A1))₂, —N(R^(A1))₂, and a nitrogen protecting group;

k is 0, 1, 2, 3, or 4;

l is 1, 2, 3, 4, or 5;

Q and U are taken together to be —NR^(A)(C═O)— or —(C═O)NR^(A)—; and

R^(D) is an electrophilic moiety as described herein.

In certain embodiments, the subject is administered compound (A-1):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-2):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-3):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-4):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-5):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-6):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-7):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-8):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-9):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-10):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-11):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-12):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-13):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-14):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-15):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-16):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-17):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is administered compound (A-18):

or a pharmaceutically acceptable salt thereof.

Compounds of Formula (A) include a phenyl Ring A optionally substituted with one or more R^(A) groups. In certain embodiments, k is 0. In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, k is 2. In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, k is 3. In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, k is 4. In certain embodiments, Ring A is of the formula:

In compounds of Formula (A), Ring A may be substituted with one or more R^(A) groups. In certain embodiments, at least one R^(A) is H. In certain embodiments, at least two R^(A) groups are H. In certain embodiments, at least three R^(A) groups are H. In certain embodiments, at least four R^(A) groups are H. In certain embodiments, at least one R^(A) is not H. In certain embodiments, at least two R^(A) groups are not H. In certain embodiments, at least three R^(A) groups are not H. In certain embodiments, at least one R^(A) is halogen. In certain embodiments, at least one R^(A) is F. In certain embodiments, at least one R^(A) is Cl. In certain embodiments, at least one R^(A) is Br. In certain embodiments, at least one R^(A) is I (iodine). In certain embodiments, one R^(A) is F. In certain embodiments, one R^(A) is Cl. In certain embodiments, at least one R^(A) is substituted alkyl. In certain embodiments, at least one R^(A) is unsubstituted alkyl. In certain embodiments, at least one R^(A) is substituted C₁₋₆ alkyl. In certain embodiments, at least one R^(A) is unsubstituted C₁₋₆ alkyl. In certain embodiments, at least one R^(A) is methyl. In certain embodiments, at least one R^(A) is ethyl. In certain embodiments, at least one R^(A) is propyl. In certain embodiments, at least one R^(A) is butyl. In certain embodiments, at least one R^(A) is substituted carbocyclyl. In certain embodiments, at least one R^(A) is unsubstituted carbocyclyl. In certain embodiments, at least one R^(A) is —OR^(A1). In certain embodiments, at least one R^(A) is —O(C₁₋₆ alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^(A) is —OMe. In certain embodiments, at least one R^(A) is —OH. In certain embodiments, at least one R^(A) is —N(R^(A1))₂. In certain embodiments, at least one R^(A) is —NH₂. In certain embodiments, at least one R^(A) is —CN. In certain embodiments, at least one R^(A) is —C(═O)R^(A1). In certain embodiments, at least one R^(A) is acetyl. In certain embodiments, at least one R^(A) is —C(═O)OR^(A1). In certain embodiments, at least one R^(A) is —C(═O)N(R^(A1))₂. In certain embodiments, at least one R^(A) is —C(═O)NHR^(A1). In certain embodiments, at least one R^(A) is —C(═O)NH(C₁₋₆ alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^(A) is —C(═O)NHMe. In certain embodiments, at least one R^(A) is —C(═O)NH₂. In certain embodiments, at least one R^(A) is —NO₂. In certain embodiments, at least one R^(A) is —NR^(A1)C(═O)R^(A1). In certain embodiments, at least one R^(A) is —NR^(A1)C(═O)OR^(A1). In certain embodiments, at least one R^(A1) is —NR^(A1)S(═O)₂R^(A1). In certain embodiments, at least one R^(A) is —NHS(═O)₂R^(A1). In certain embodiments, at least one R^(A) is —NHS(═O)₂(C₁₋₆ alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^(A) is —NHS(═O)₂Me. In certain embodiments, at least one R^(A) is —S(═O)₂R^(A1). In certain embodiments, at least one R^(A) is —S(═O)₂N(R^(A1))₂. In certain embodiments, at least one R^(A) is —S(═O)₂N(R^(A1))₂. In certain embodiments, at least one R^(A) is —S(═O)₂N(C₁₋₆ alkyl)₂. In certain embodiments, at least one R^(A) is —S(═O)₂NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(A) is —S(═O)₂NH(t-Bu). In certain embodiments, at least one R^(A) is —S(═O)₂NH₂.

In certain embodiments, R^(A) is —OR^(A1); and k is 1. In certain embodiments, R^(A) is —O(C₁₋₆ alkyl); and k is 1. In certain embodiments, R^(A) is —OMe; and k is 1. In certain embodiments, R^(A) is —OH; and k is 1.

In certain embodiments, R^(A) is substituted C₁₋₆ alkyl; and k is 1. In certain embodiments, R^(A) is unsubstituted C₁₋₆ alkyl; and k is 1. In certain embodiments, R^(A) is methyl; and k is 1. In certain embodiments, R^(A) is —CF₃; and k is 1. In certain embodiments, R^(A) is ethyl; and k is 1. In certain embodiments, R^(A) is propyl; and k is 1. In certain embodiments, R^(A) is butyl; and k is 1. In certain embodiments, R^(A) is propyl; and k is 1. In certain embodiments, R^(A) is butyl; and k is 1.

In certain embodiments, R^(A) is halogen; and k is 1. In certain embodiments, R^(A) is F; and k is 1. In certain embodiments, R^(A) is Cl; and k is 1. In certain embodiments, R^(A) is Br; and k is 1. In certain embodiments, R^(A) is I (iodine); and k is 1.

In certain embodiments, one instance of R^(A) is halogen; another instance of R^(A) is substituted C₁₋₆ alkyl; and k is 2. In certain embodiments, one instance of R^(A) is F; another instance of R^(A) is substituted C₁₋₆ alkyl; and k is 2. In certain embodiments, one instance of R^(A) is Cl; another instance of R^(A) is substituted C₁₋₆ alkyl; and k is 2. In certain embodiments, one instance of R^(A) is halogen; another instance of R^(A) is unsubstituted C₁₋₆ alkyl; and k is 2. In certain embodiments, one instance of R^(A) is F; another instance of R^(A) is unsubstituted C₁₋₆ alkyl; and k is 2. In certain embodiments, one instance of R^(A) is Cl; another instance of R^(A) is unsubstituted C₁₋₆ alkyl; and k is 2. In certain embodiments, one instance of R^(A) is halogen; another instance of R^(A) is methyl; and k is 2. In certain embodiments, one instance of R^(A) is F; another instance of R^(A) is methyl; and k is 2. In certain embodiments, one instance of R^(A) is Cl; another instance of R^(A) is methyl; and k is 2. In certain embodiments, one instance of R^(A) is halogen; another instance of R^(A) is —CF₃; and k is 2. In certain embodiments, one instance of R^(A) is F; another instance of R^(A) is —CF₃; and k is 2. In certain embodiments, one instance of R^(A) is Cl; another instance of R^(A) is CF₃; and k is 2.

In certain embodiments, at least one R^(A1) is H. In certain embodiments, at least one R^(A1) is substituted acyl. In certain embodiments, at least one R^(A1) is unsubstituted acyl. In certain embodiments, at least one R^(A1) is acetyl. In certain embodiments, at least one R^(A1) is substituted alkyl. In certain embodiments, at least one R^(A1) is unsubstituted alkyl. In certain embodiments, at least one R^(A1) is C₁₋₆ alkyl. In certain embodiments, at least one R^(A1) is methyl. In certain embodiments, at least one R^(A1) is ethyl. In certain embodiments, at least one R^(A1) is propyl. In certain embodiments, at least one R^(A1) is butyl. In certain embodiments, at least one R^(A1) is substituted alkenyl. In certain embodiments, at least one R^(A1) is unsubstituted alkenyl. In certain embodiments, at least one R^(A1) is substituted alkynyl. In certain embodiments, at least one R^(A1) is unsubstituted alkynyl. In certain embodiments, at least one R^(A1) is substituted carbocyclyl. In certain embodiments, at least one R^(A1) is unsubstituted carbocyclyl. In certain embodiments, at least one R^(A1) is substituted heterocyclyl. In certain embodiments, at least one R^(A1) is unsubstituted heterocyclyl. In certain embodiments, at least one R^(A1) is substituted aryl. In certain embodiments, at least one R^(A1) is unsubstituted aryl. In certain embodiments, at least one R^(A1) is substituted phenyl. In certain embodiments, at least one R^(A1) is unsubstituted phenyl. In certain embodiments, at least one R^(A1) is substituted heteroaryl. In certain embodiments, at least one R^(A1) is unsubstituted heteroaryl. In certain embodiments, at least one R^(A1) is substituted pyridyl. In certain embodiments, at least one R^(A1) is unsubstituted pyridyl. In certain embodiments, at least one R^(A1) is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^(A1) is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^(A1) is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^(A1) is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^(A1) is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^(A1) is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.

In compounds of Formula (A), two R^(A1) groups may be joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring. In certain embodiments, two R^(A1) groups are joined to form a substituted carbocyclic ring. In certain embodiments, two R^(A1) groups are joined to form an unsubstituted carbocyclic ring. In certain embodiments, two R^(A1) groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^(A1) groups are joined to form an unsubstituted heterocyclic ring. In certain embodiments, two R^(A1) groups are joined to form a substituted aryl ring. In certain embodiments, two R^(A1) groups are joined to form an unsubstituted aryl ring. In certain embodiments, two R^(A1) groups are joined to form a substituted phenyl ring. In certain embodiments, two R^(A1) groups are joined to form an unsubstituted phenyl ring. In certain embodiments, two R^(A1) groups are joined to form a substituted heteroaryl ring. In certain embodiments, two R^(A1) groups are joined to form an unsubstituted heteroaryl ring.

Compounds of Formula (A) include a phenyl Ring C optionally substituted with one or more R^(B) groups. In certain embodiments, l is 1. In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, l is 2. In certain embodiments, Ring C is of the formula:

In certain embodiments, l is 2. In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, l is 3. In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, l is 4. In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, l is 5. In certain embodiments, Ring C is of the formula:

In compounds of Formula (A), Ring C may be substituted with one or more R^(B) groups. In certain embodiments, at least one R^(B) is H. In certain embodiments, at least two R^(B) groups are H. In certain embodiments, at least three R^(B) groups are H. In certain embodiments, at least four R^(B) groups are H. In certain embodiments, at least one R^(B) is not H. In certain embodiments, at least two R^(B) groups are not H. In certain embodiments, at least three R^(B) groups are not H. In certain embodiments, at least one R^(B) is halogen. In certain embodiments, at least one R^(B) is F. In certain embodiments, at least one R^(B) is Cl. In certain embodiments, at least one R^(B) is Br. In certain embodiments, at least one R^(B) is I (iodine). In certain embodiments, one R^(B) is F. In certain embodiments, one R^(B) is Cl. In certain embodiments, at least one R^(B) is substituted alkyl. In certain embodiments, at least one R^(B) is unsubstituted alkyl. In certain embodiments, at least one R^(B) is substituted C₁₋₆ alkyl. In certain embodiments, at least one R^(B) is unsubstituted C₁₋₆ alkyl. In certain embodiments, at least one R^(B) is methyl. In certain embodiments, at least one R^(B) is ethyl. In certain embodiments, at least one R^(B) is propyl. In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is butyl. In certain embodiments, at least one R^(B) is substituted carbocyclyl. In certain embodiments, at least one R^(B) is unsubstituted carbocyclyl. In certain embodiments, at least one R^(B) is substituted heterocyclyl. In certain embodiments, at least one R^(B) is unsubstituted heterocyclyl. In certain embodiments, at least one R^(B) is substituted piperidine. In certain embodiments, at least one R^(B) is unsubstituted piperidine. In certain embodiments, at least one R^(B) substituted piperizine. In certain embodiments, at least one R^(B) unsubstituted piperizine. In certain embodiments, at least one R^(B) substituted pyrrolidine. In certain embodiments, at least one R^(B) unsubstituted pyrrolidine. In certain embodiments, at least one R^(B) is substituted morpholine. In certain embodiments, at least one R^(B) is unsubstituted morpholine. In certain embodiments, at least one R^(B) is substituted diazapane. In certain embodiments, at least one R^(B) is unsubstituted diazapane. In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is substituted —(CH₂)(heterocyclyl). In certain embodiments, at least one R^(B) is unsubstituted —(CH₂)(heterocyclyl). In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is substituted —(CH₂)₂(heterocyclyl). In certain embodiments, at least one R^(B) is unsubstituted —(CH₂)₂(heterocyclyl). In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is substituted —(CH₂)₃(heterocyclyl). In certain embodiments, at least one R^(B) is unsubstituted —(CH₂)₃(heterocyclyl). In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is substituted aryl. In certain embodiments, at least one R^(B) is unsubstituted aryl. In certain embodiments, at least one R^(B) is substituted phenyl. In certain embodiments, at least one R^(B) is unsubstituted phenyl. In certain embodiments, at least one R^(B) is substituted heteroaryl. In certain embodiments, at least one R^(B) is unsubstituted heteroaryl. In certain embodiments, at least one R^(B) is substituted pyridyl. In certain embodiments, at least one R^(B) is unsubstituted pyridyl. In certain embodiments, at least one R^(B) is substituted imidazole. In certain embodiments, at least one R^(B) is unsubstituted imidazole. In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is —OR^(A1). In certain embodiments, at least one R^(B) is —O(C₁₋₆ alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^(B) is —OMe. In certain embodiments, at least one R^(B) is —OPh. In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is —OH. In certain embodiments, at least one R^(B) is —N(R^(A1))₂. In certain embodiments, at least one R^(B) is —NEt₂. In certain embodiments, at least one R^(B) is —NMe₂. In certain embodiments, at least one R^(B) is —NHtBu. In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is —NH₂. In certain embodiments, at least one R^(B) is —CN. In certain embodiments, at least one R^(B) is —C(═O)R^(A1). In certain embodiments, at least one R^(B) is acetyl. In certain embodiments, at least one R^(B) is —C(═O)OR^(A1). In certain embodiments, at least one R^(B) is —C(═O)N(R^(A1))₂. In certain embodiments, at least one R^(B) is —C(═O)NHR^(A1). In certain embodiments, at least one R^(B) is —C(═O)NH(C₁₋₆ alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^(B) is —C(═O)NHMe. In certain embodiments, at least one R^(B) is —C(═O)NH₂. In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is

In certain embodiments, at least one R^(B) is —NO₂. In certain embodiments, at least one R^(B) is —NR^(A1)C(═O)R^(A1). In certain embodiments, at least one R^(B) is —NR^(A1)C(═O)OR^(A1). In certain embodiments, at least one R^(B) is —NR^(A1)S(═O)₂R^(A1). In certain embodiments, at least one R^(B) is —NHS(═O)₂R^(A1). In certain embodiments, at least one R^(B) is —NHS(═O)₂(C₁₋₆ alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^(B) is —NHS(═O)₂Me. In certain embodiments, at least one R^(B) is —S(═O)₂R^(A1). In certain embodiments, at least one R^(B) is —S(═O)₂N(R^(A1))₂. In certain embodiments, at least one R^(B) is —S(═O)₂N(R^(A1))₂. In certain embodiments, at least one R^(B) is —S(═O)₂N(C₁₋₆ alkyl)₂. In certain embodiments, at least one R^(B) is —S(═O)₂NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(B) is —S(═O)₂NH(t-Bu). In certain embodiments, at least one R^(B) is —S(═O)₂NH₂.

In certain embodiments, R^(B) is substituted or unsubstituted C₁₋₆alkyl; and l is 1. In certain embodiments, R^(B) is substituted or unsubstituted C₁₋₆alkyl; l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is substituted or unsubstituted C₁₋₆alkyl; l is 1; and R^(B) is para to the point of attachment of U. In certain embodiments, R^(B) is C₁₋₆alkyl substituted with one —CN group; and l is 1. In certain embodiments, R^(B) is C₁₋₆alkyl substituted with one —CN group; l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is C₁₋₆alkyl substituted with one —CN group; l is 1; and R^(B) is para to the point of attachment of U. In certain embodiments, R^(B) is

and l is 1. In certain embodiments, R^(B) is

l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is

l is 1; and R^(B) is para to the point of attachment of U. In certain embodiments, R^(B) is substituted or unsubstituted CH₂(piperazinyl); and l is 1. In certain embodiments, R^(B) is substituted or unsubstituted CH₂(piperazinyl); l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is substituted or unsubstituted —CH₂-(piperazinyl); l is 1; and R^(B) is para to the point of attachment of U. In certain embodiments, R^(B) is

and l is 1. In certain embodiments, R^(B) is

l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is

l is 1; and R^(B) is para to the point of attachment of U. In certain embodiments, R^(B) is haloalkyl; and l is 1. In certain embodiments, R^(B) is haloalkyl; l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is haloalkyl; l is 1; and R^(B) is para to the point of attachment of U. In certain embodiments, R^(B) is —CF₃; and l is 1. In certain embodiments, R^(B) is —CF₃; l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is —CF₃; l is 1; and R^(B) is para to the point of attachment of U. In certain embodiments, R^(B) is substituted or unsubstituted imidazoyl; and l is 1. In certain embodiments, R^(B) is substituted or unsubstituted imidazoyl; l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is substituted or unsubstituted imidazoyl; l is 1; and R^(B) is para to the point of attachment of U. In certain embodiments, R^(B) is

and l is 1. In certain embodiments, R^(B) is

l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is

l is 1; and R^(B) is para to the point of attachment of U. In certain embodiments, R^(B) is substituted or unsubstituted piperazinyl; and l is 1. In certain embodiments, R^(B) is substituted or unsubstituted piperazinyl; l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is substituted or unsubstituted piperazinyl; l is 1; and R^(B) is para to the point of attachment of U. In certain embodiments, R^(B) is

and l is 1. In certain embodiments, R^(B) is

l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is

l is 1; and R^(B) is para to the point of attachment of U. In certain embodiments, R^(B) is substituted or unsubstituted morpholine; and l is 1. In certain embodiments, R^(B) is substituted or unsubstituted morpholine; l is 1; and R^(B) is meta to the point of attachment of U. In certain embodiments, R^(B) is substituted or unsubstituted morpholine; l is 1; and R^(B) is para to the point of attachment of U.

In certain embodiments, at least one R^(B) group is substituted or unsubstituted C₁₋₆alkyl; and l is 2. In certain embodiments, at least one R^(B) group is substituted or unsubstituted C₁₋₆alkyl; l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is substituted or unsubstituted C₁₋₆alkyl; l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, at least one R^(B) group is C₁₋₆alkyl substituted with one —CN group; and l is 2. In certain embodiments, at least one R^(B) group is C₁₋₆alkyl substituted with one —CN group; l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is C₁₋₆alkyl substituted with one —CN group; l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, at least one R^(B) group is

and l is 2. In certain embodiments, at least one R^(B) group is

l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is

l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, at least one R^(B) group is substituted or unsubstituted —CH₂-(piperazinyl); and l is 2. In certain embodiments, at least one R^(B) group is substituted or unsubstituted —CH₂-(piperazinyl); l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is substituted or unsubstituted —CH₂(piperazinyl); l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, at least one R^(B) group is

and l is 2. In certain embodiments, at least one R^(B) group is

l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is

l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, at least one R^(B) group is haloalkyl; and l is 2. In certain embodiments, at least one R^(B) group is haloalkyl; l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is haloalkyl; l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, at least one R^(B) group is —CF₃; and l is 2. In certain embodiments, at least one R^(B) group is —CF₃; l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is CF₃; l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, at least one R^(B) group is substituted or unsubstituted imidazoyl; and l is 2. In certain embodiments, at least one R^(B) group is substituted or unsubstituted imidazoyl; l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is substituted or unsubstituted imidazoyl; l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, at least one R^(B) group is

and l is 2. In certain embodiments, at least one R^(B) group is

l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is

l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, at least one R^(B) group is substituted or unsubstituted piperazinyl; and l is 2. In certain embodiments, at least one R^(B) group is substituted or unsubstituted piperazinyl; l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is substituted or unsubstituted piperazinyl; l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, at least one R^(B) group is

and l is 2. In certain embodiments, at least one R^(B) group is

l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is

l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, at least one R^(B) group is substituted or unsubstituted morpholine; and l is 2. In certain embodiments, at least one R^(B) group is substituted or unsubstituted morpholine; l is 2; and at least one R^(B) is meta to the point of attachment of U. In certain embodiments, at least one R^(B) group is substituted or unsubstituted morpholine; l is 2; and one R^(B) is para to the point of attachment of U. In certain embodiments, two R^(B) groups are substituted or unsubstituted morpholine; l is 2; and both R^(B) groups are meta to the point of attachment of U.

In compounds of Formula (A), Q and U are taken together to represent a divalent linker moiety. In certain embodiments, Q and U are taken together to represent

In certain embodiments, Q and U are taken together to represent

In certain embodiments, Q and U are taken together to represent

In certain embodiments, Q and U are taken together to represent

Formula (A) includes a pyridine or pyrimidine ring as Ring B. In certain embodiments, each instance of A included in Ring B is carbon. In certain embodiments, one instance of A included in Ring B is carbon, and the other instance of A included in Ring B is nitrogen. In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

Formula (A) may include one or more R^(Y) groups. When Formula (A) includes two instances of R^(Y), the two instances of R^(Y) may be the same or different from each other. In certain embodiments, at least one instance of R^(Y) is H. In certain embodiments, each instance of R^(Y) is H. In certain embodiments, at least one instance of R^(Y) is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R^(Y) is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, at least one instance of R^(Y) is Me. In certain embodiments, at least one instance of R^(Y) is substituted methyl (e.g., —CF₃ or Bn). In certain embodiments, at least one instance of R^(Y) is Et, substituted ethyl (e.g., perfluoroethyl), Pr, substituted propyl (e.g., perfluoropropyl), Bu, or substituted butyl (e.g., perfluorobutyl).

In compounds of Formula (A), the pyridine or pyrimidine ring may be substituted with one or more R^(X) groups. When Formula (A) includes two instances of R^(X), the two instances of R^(X) may be the same or different from each other. In certain embodiments, at least one R^(X) is substituted carbocyclyl. In certain embodiments, at least one R^(X) is unsubstituted carbocyclyl. In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is substituted heterocyclyl. In certain embodiments, at least one R^(X) is unsubstituted heterocyclyl. In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is substituted aryl. In certain embodiments, at least one R^(X) is unsubstituted aryl. In certain embodiments, at least one R^(X) is substituted phenyl. In certain embodiments, at least one R^(X) is unsubstituted phenyl. In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is substituted heteroaryl. In certain embodiments, at least one R^(X) is unsubstituted heteroaryl. In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is —N(R^(A1))(R^(Xa)). In certain embodiments, at least one R^(X) is —NH₂. In certain embodiments, at least one R^(X) is —NH(3-6 membered cycloalkyl) where the cycloalkyl is substituted or unsubstituted. In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is —NH(C₁₋₆alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^(X) is —N(C₁₋₆alkyl)₂ where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is —NH(acyl). In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is —NHC(═O)(3-6 membered cycloalkyl) where the cycloalkyl is substituted or unsubstituted. In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is —NHC(═O)(C₁₋₆alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is

In certain embodiments, at least one R^(X) is —N(R^(A1))N(R^(A1))₂. In certain embodiments, at least one R^(X) is —NHN(R^(A1))₂. In certain embodiments, at least one R^(X) is —NHNH(acyl). In certain embodiments, at least one R^(X) is —NHNHC(═O)Me. In certain embodiments, at least one R^(X) is —NHN(C₁₋₆alkyl)₂ where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^(X) is —NHNMe₂.

In compounds of Formula (A), R^(X) may be substituted with one or more R^(Xa) groups. Each instance of R^(Xa) is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —S(═O)R^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), —S(═O)₂N(R^(A1))₂, —N(R^(A1))₂, and a nitrogen protecting group; wherein each occurrence of R^(A1) is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R^(A1) groups are joined to form an optionally substituted heterocyclic ring.

In certain embodiments, at least one R^(Xa) is H. In certain embodiments, all R^(Xa) groups are H. In certain embodiments, at least one R^(Xa) is substituted alkyl. In certain embodiments, at least one R^(Xa) is substituted C₁₋₆ alkyl. In certain embodiments, at least one R^(Xa) is substituted methyl. In certain embodiments, at least one R^(Xa) is unsubstituted alkyl. In certain embodiments, at least one R^(Xa) is unsubstituted C₁₋₆ alkyl. In certain embodiments, at least one R^(Xa) is methyl. In certain embodiments, at least one R^(Xa) is ethyl. In certain embodiments, at least one R^(Xa) is propyl. In certain embodiments, at least one R^(Xa) is butyl. In certain embodiments, at least one R^(Xa) is substituted alkenyl. In certain embodiments, at least one R^(Xa) is unsubstituted alkenyl. In certain embodiments, at least one R^(Xa) is substituted alkynyl. In certain embodiments, at least one R^(Xa) is unsubstituted alkynyl. In certain embodiments, at least one R^(Xa) is substituted carbocyclyl. In certain embodiments, at least one R^(Xa) is unsubstituted carbocyclyl. In certain embodiments, at least one R^(Xa) is substituted heterocyclyl. In certain embodiments, at least one R^(Xa) is unsubstituted heterocyclyl. In certain embodiments, at least one R^(Xa) is substituted aryl. In certain embodiments, at least one R^(Xa) is unsubstituted aryl. In certain embodiments, at least one R^(Xa) is substituted phenyl. In certain embodiments, at least one R^(Xa) is unsubstituted phenyl. In certain embodiments, at least one R^(Xa) is substituted heteroaryl. In certain embodiments, at least one R^(Xa) is unsubstituted heteroaryl. In certain embodiments, at least one R^(Xa) is —C(═O)R^(A1). In certain embodiments, at least one R^(Xa) is —C(═O)H. In certain embodiments, at least one R^(Xa) is acetyl. In certain embodiments, at least one R^(Xa) is —C(═O)(C₁₋₆alkyl). In certain embodiments, at least one R^(Xa) is —C(═O)OR^(A1). In certain embodiments, at least one R^(Xa) is —C(═O)OH. In certain embodiments, at least one R^(Xa) is —C(═O)O(C₁₋₆alkyl). In certain embodiments, at least one R^(Xa) is —C(═O)N(R^(A1))₂. In certain embodiments, at least one R^(Xa) is —C(═O)NHR^(A1). In certain embodiments, at least one R^(Xa) is —C(═O)N(C₁₋₆ alkyl)₂. In certain embodiments, at least one R^(Xa) is —C(═O)NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(Xa) is —C(═O)NH₂. In certain embodiments, at least one R^(Xa) is —S(═O)R^(A1). In certain embodiments, at least one R^(Xa) is —S(═O)(C₁₋₆alkyl). In certain embodiments, at least one R^(Xa) is —S(═O)N(R^(A1))₂. In certain embodiments, at least one R^(Xa) is —S(═O)NH(R^(A1)). In certain embodiments, at least one R^(Xa) is —S(═O)NH₂. In certain embodiments, at least one R^(Xa) is —S(═O)N(C₁₋₆alkyl)₂. In certain embodiments, at least one R^(Xa) is —S(═O)NH(C₁₋₆alkyl). In certain embodiments, at least one R^(Xa) is —S(═O)₂R^(A1). In certain embodiments, at least one R^(Xa) is —S(═O)₂(C₁₋₆alkyl). In certain embodiments, at least one R^(Xa) is —S(═O)₂OR^(A1). In certain embodiments, at least one R^(Xa) is —S(═O)₂OH. In certain embodiments, at least one R^(Xa) is —S(═O)₂N(R^(A1))₂. In certain embodiments, at least one R^(Xa) is —S(═O)₂NH(R^(A1)). In certain embodiments, at least one R^(Xa) is —S(═O)₂NH₂. In certain embodiments, at least one R^(Xa) is —S(═O)₂N(C₁₋₆alkyl)₂. In certain embodiments, at least one R^(Xa) is —S(═O)₂NH(C₁₋₆alkyl). In certain embodiments, at least one R^(Xa) is —N(R^(A1))₂. In certain embodiments, at least one R ^(Xa) is —NH(R^(A1)). In certain embodiments, at least one R^(Xa) is —NH(acyl). In certain embodiments, at least one R^(Xa) is —NHC(═O)Me. In certain embodiments, at least one R^(Xa) is —N(C₁₋₆alkyl)₂ where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^(Xa) is —NMe₂.

In compounds of Formula (A), R^(X) may be substituted with one or more R^(Xc) groups. Each instance of R^(Xc) is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —CN, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —NO₂, —N₃, —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1), —NR^(A1)C(═)N(R^(A1))₂, —NR^(A1)S(═O)₂R^(A1), —NR^(A1)S(═O)R^(A1), —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —S(═O)R^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂N(^(RA1))₂; wherein each occurrence of R^(A1) is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R^(A1) groups are joined to form an optionally substituted heterocyclic ring.

In certain embodiments, at least one R^(Xc) is H. In certain embodiments, all R^(Xc) groups are H. In certain embodiments, at least one R^(Xc) is substituted alkyl. In certain embodiments, at least one R^(Xc) is substituted C₁₋₆ alkyl. In certain embodiments, at least one R^(Xc) is substituted methyl. In certain embodiments, at least one R^(Xc) is unsubstituted alkyl. In certain embodiments, at least one R^(Xc) is unsubstituted C₁₋₆ alkyl. In certain embodiments, at least one R^(Xc) is methyl. In certain embodiments, at least one R^(Xc) is ethyl. In certain embodiments, at least one R^(Xc) is propyl. In certain embodiments, at least one R^(Xc) is butyl. In certain embodiments, at least one R^(Xc) is substituted alkenyl. In certain embodiments, at least one R^(Xc) is unsubstituted alkenyl. In certain embodiments, at least one R^(Xc) is substituted alkynyl. In certain embodiments, at least one R^(Xc) is unsubstituted alkynyl. In certain embodiments, at least one R^(Xc) is substituted carbocyclyl. In certain embodiments, at least one R^(Xc) is unsubstituted carbocyclyl. In certain embodiments, at least one R^(Xc) is substituted heterocyclyl. In certain embodiments, at least one R^(Xc) is unsubstituted heterocyclyl. In certain embodiments, at least one R^(Xc) is substituted aryl. In certain embodiments, at least one R^(Xc) is unsubstituted aryl. In certain embodiments, at least one R^(Xc) is substituted phenyl. In certain embodiments, at least one R^(Xc) is unsubstituted phenyl. In certain embodiments, at least one R^(Xc) is substituted heteroaryl. In certain embodiments, at least one R^(Xc) is unsubstituted heteroaryl. In certain embodiments, at least one R^(Xc) is —OR^(A1). In certain embodiments, at least one R^(Xc) is —OH. In certain embodiments, at least one R^(Xc) is —O(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —N(R^(A1))₂. In certain embodiments, at least one R^(Xc) is —NH(R^(A1)). In certain embodiments, at least one R^(Xc) is —N(C₁₋₆alkyl)₂. In certain embodiments, at least one R^(Xc) is —NH(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —NH₂. In certain embodiments, at least one R^(Xc) is —SR^(A1). In certain embodiments, at least one R^(Xc) is —SH. In certain embodiments, at least one R^(Xc) is —S(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —CN. In certain embodiments, at least one R^(Xc) is —NO₂. In certain embodiments, at least one R^(Xc) is —N₃. In certain embodiments, at least one R^(Xc) is —NR^(A1)C(═O)R^(A1). In certain embodiments, at least one R^(Xc)is —NHC(═O)R^(A1). In certain embodiments, at least one R^(Xc) is —NHC(═O)(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —NR^(A1)C(═O)OR^(A1). In certain embodiments, at least one R^(Xc) is —NHC(═O)OR^(A1). In certain embodiments, at least one R^(Xc) is —NR^(A1)C(═O)O(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —NR^(A1)C(═O)N(R^(A1))₂. In certain embodiments, at least one R^(Xc) is —NHC(═O)N(C₁₋₆alkyl)₂. In certain embodiments, at least one R^(Xc) is —NHC(═O)NH₂. In certain embodiments, at least one R^(Xc) is —NR^(A1)S(═O)₂R^(A1). In certain embodiments, at least one R^(Xc) is —NHS(═O)₂R^(A1). In certain embodiments, at least one R^(Xc) is —NHS(═O)₂(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is NR^(A1)S(═O)R^(A1). In certain embodiments, at least one R^(Xc) is —NR^(A1)S(═O)(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —NHS(═O)(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —OC(═O)R^(A1). In certain embodiments, at least one R^(Xc) is —OC(═O)(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —OC(═O)OR^(A1). In certain embodiments, at least one R^(Xc) is —OC(═O)O(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —OC(═O)N(R^(A1))₂. In certain embodiments, at least one R^(Xc) is —C(═O)NH(R^(A1)). In certain embodiments, at least one R^(Xc) is —C(═O)N(C₁₋₆alkyl)₂. In certain embodiments, at least one R^(Xc) is —C(═O)R^(A1). In certain embodiments, at least one R^(Xc) is —C(═O)H. In certain embodiments, at least one R^(Xc) is acetyl. In certain embodiments, at least one R^(Xc) is —C(═O)(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —C(═O)OR^(A1). In certain embodiments, at least one R^(Xc) is —C(═O)OH. In certain embodiments, at least one R^(Xc) is —C(═O)O(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —C(═O)N(R^(A1))₂. In certain embodiments, at least one R^(Xc) is —C(═O)NHR^(A1). In certain embodiments, at least one R^(Xc) is —C(═O)N(C₁₋₆ alkyl)₂. In certain embodiments, at least one R^(Xc) is —C(═O)NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(Xc) is —C(═O)NH₂. In certain embodiments, at least one R^(Xc) is —S(═O)R^(A1). In certain embodiments, at least one R^(Xc) is —S(═O)(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —S(═O)N(R^(A1))₂. In certain embodiments, at least one R^(Xc) is ——S(═O)NH(R^(A1)). In certain embodiments, at least one R^(Xc) is —S(═O)NH₂. In certain embodiments, at least one R^(Xc) is —S(═O)N(C₁₋₆alkyl)₂. In certain embodiments, at least one R^(Xc) is —S(═O)NH(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —S(═O)₂R^(A1). In certain embodiments, at least one R^(Xc) is —S(═O)₂(C₁₋₆alkyl). In certain embodiments, at least one R^(Xc) is —S(═O)₂OR^(A1). In certain embodiments, at least one R^(Xc) is —S(═O)₂OH. In certain embodiments, at least one R^(Xc) is —S(═O)₂N(R^(A1))₂. In certain embodiments, at least one R^(Xc) is —S(═O)₂NH(R^(A1)). In certain embodiments, at least one R^(Xc) is —S(═O)₂NH₂. In certain embodiments, at least one R^(Xc) is —S(═O)₂N(C₁₋₆alkyl)₂. In certain embodiments, at least one R^(Xc) is —S(═O)₂NH(C₁₋₆alkyl).

In compounds of Formula (A), R^(D) is an optional electrophilic moiety that is attached to the pyridyl ring. In certain embodiments, R^(D) is any one of Formulae (i-1)-(i-18):

R^(D1) is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, CN, —NO₂, —OR^(D1a), —N(R^(D1a))₂, —SR^(D1a), —CH₂OR^(D1a), —CH₂N(R^(D1a))₂, —CH₂SR^(D1a), —C(═O)R^(D1a), —C(═O)OR^(D1a), —C(═O)SR^(D1a), —C(═O)N(R^(D1a))₂, —C(═S)R^(D1a), —C(═S)OR^(D1a), —C(═S)SR^(D1a), —C(═S)N(R^(D1a))₂, —C(═NR^(D1a))R^(D1a), —C(═NR^(D1a))OR^(D1a), —C(═NR^(D1a))SR^(D1a), and —C(═NR^(D1a))N(R^(D1a))₂ wherein each occurrence of R^(D1a) is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^(D1a) groups are joined to form an optionally substituted heterocyclic ring;

R^(D2) is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^(D2a), —N(R^(D2a))₂, —SR^(D2a), —CH₂OR^(D2a), —CH₂N(R^(D2a))₂, —CH₂SR^(D2a), —C(═O)R^(D2a), —C(═O)OR^(D2a), —C(═O)SR^(D2a), —C(═O)N(R^(D2a))₂, —C(═S)R^(D2a), —C(═S)OR^(D2a), —C(═S)SR^(D2a), —C(═S)N(R^(D2a))₂, —C(═NR^(D2a))R^(D2a), —C(═NR^(D2a))OR^(D2a), —C(═NR^(D2a))SR^(D2a), and —C(═NR^(D2a))N(R^(D2a))₂, wherein each occurrence of R^(D2a) is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^(D2a) groups are joined to form an optionally substituted heterocyclic ring;

R^(D3) is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^(D3a), —N(R^(D3a))₂, —SR^(D3a), —CH₂OR^(D3a), —CH₂N(R^(D3a))₂, —CH₂SR^(D3a), —C(═O)R^(D3a), —C(═O)OR^(D3a), —C(═O)SR^(D3a), —C(═O)N(R^(D3a))₂, —C(═S)R^(D3a), —C(═S)OR^(D3a), —C(═S)SR^(D3a), —C(═S)N(R^(D3a))₂, —C(═NR^(D3a))R^(D3a), —C(═NR^(D3a))OR^(D3a), —C(═NR^(D3a))SR^(D3a), and —C(═NR^(D3a))N(R^(D3a))₂, wherein each occurrence of R^(D3a) is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^(D3a) groups are joined to form an optionally substituted heterocyclic ring;

optionally R^(D1) and R^(D3), or R^(D2) and R^(D3), or R^(D1) and R^(D2) are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

R^(D4) is a leaving group;

R^(D5) is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group;

Y^(Z) is —O—, —S—, or —NR^(D6)—, wherein R^(D6) is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group;

a is 1 or 2;

z is 0, 1, 2, 3, 4, 5, or 6; and

optionally R^(D5) and one R^(C) are joined to form an optionally substituted heterocyclic ring.

In certain embodiments, R^(D) comprises a Michael acceptor moiety. This Michael acceptor moiety may react with a cysteine or other nucleophilic residue to allow covalent attachment of the compound to the target. In certain embodiments, the covalent attachment is irreversible. In other embodiments, the covalent attachment is reversible. In certain embodiments, R^(D) is of Formula (i-1). In certain embodiments, R^(D) is of Formula (i-2). In certain embodiments, R^(D) is of Formula (i-3). In certain embodiments, R^(D) is of Formula (i-4). In certain embodiments, R^(D) is of Formula (i-5). In certain embodiments, R^(D) is of Formula (i-6). In certain embodiments, R^(D) is of Formula (i-7). In certain embodiments, R^(D) is of Formula (i-8). In certain embodiments, R^(D) is of Formula (i-9). In certain embodiments, R^(D) is of Formula (i-10). In certain embodiments, R^(D) is of Formula (i-11). In certain embodiments, R^(D) is of Formula (i-12). In certain embodiments, R^(D) is of Formula (i-13). In certain embodiments, R^(D) is of Formula (i-14). In certain embodiments, R^(D) is of Formula (i-15). In certain embodiments, R^(D) is of Formula (i-16). In certain embodiments, R^(D) is of Formula (i-17).

In compounds of Formula (A), R^(D) may include a substituent R^(D1). In certain embodiments, R^(D1) is H. In certain embodiments, R^(D1) is halogen. In certain embodiments, R^(D1) is F. In certain embodiments, R^(D1) is Cl. In certain embodiments, R^(D1) is Br. In certain embodiments, R^(D1) is I (iodine). In certain embodiments, R^(D1) is substituted acyl. In certain embodiments, R^(D1) is unsubstituted acyl. In certain embodiments, R^(D1) is acetyl. In certain embodiments, R^(D1) is substituted alkyl. In certain embodiments, R^(D1) is unsubstituted alkyl. In certain embodiments, R^(D1) is C₁₋₆ alkyl. In certain embodiments, R^(D1) is methyl. In certain embodiments, R^(D1) is ethyl. In certain embodiments, R^(D1) is propyl. In certain embodiments, R^(D1) is butyl. In certain embodiments, R^(D1) is substituted alkenyl. In certain embodiments, R^(D1) is unsubstituted alkenyl. In certain embodiments, R^(D1) is substituted alkynyl. In certain embodiments, R^(D1) is unsubstituted alkynyl. In certain embodiments, R^(D1) is substituted carbocyclyl. In certain embodiments, R^(D1) is unsubstituted carbocyclyl. In certain embodiments, R^(D1) is substituted heterocyclyl. In certain embodiments, R^(D1) is unsubstituted heterocyclyl. In certain embodiments, R^(D1) is substituted aryl. In certain embodiments, R^(D1) is unsubstituted aryl. In certain embodiments, R^(D1) is substituted phenyl. In certain embodiments, R^(D1) is unsubstituted phenyl. In certain embodiments, R^(D1) is substituted heteroaryl. In certain embodiments, R^(D1) is unsubstituted heteroaryl. In certain embodiments, R^(D1) is substituted pyridyl. In certain embodiments, R^(D1) is unsubstituted pyridyl. In certain embodiments, R^(D1) is —CN. In certain embodiments, R^(D1) is —NO₂. In certain embodiments, R^(D1) is —OR^(D1a). In certain embodiments, R^(D1 is —N)(R^(D1a))². In certain embodiments, R^(D1) is —SR^(D1a). In certain embodiments, R^(D1) is —CH₂OR^(D1a). In certain embodiments, R^(D1) is —CH₂N(R^(D1a))₂. In certain embodiments, R^(D1) is —CH₂SR^(D1a).

In certain embodiments, at least one R^(D1a) is H. In certain embodiments, at least one R^(D1a) is substituted acyl. In certain embodiments, at least one R^(D1a) is unsubstituted acyl. In certain embodiments, at least one R^(D1a) is acetyl. In certain embodiments, at least one R^(D1a) is substituted alkyl. In certain embodiments, at least one R^(D1a) is unsubstituted alkyl. In certain embodiments, at least one R^(D1a)is C₁₋₆ alkyl. In certain embodiments, at least one R^(D1a) is methyl. In certain embodiments, at least one R^(D1a) i s ethyl. In certain embodiments, at least one R^(D1a) is propyl. In certain embodiments, at least one R^(D1a) is butyl. In certain embodiments, at least one R^(D1a) is substituted alkenyl. In certain embodiments, at least one R^(D1a) is unsubstituted alkenyl. In certain embodiments, at least one R^(D1a) is substituted alkynyl. In certain embodiments, at least one R^(D1a) is unsubstituted alkynyl. In certain embodiments, at least one R^(D1a) is substituted carbocyclyl. In certain embodiments, at least one R^(D1a) is unsubstituted carbocyclyl. In certain embodiments, at least one R^(D1a) is substituted heterocyclyl. In certain embodiments, at least one R^(D1a) is unsubstituted heterocyclyl. In certain embodiments, at least one R^(D1a) is substituted aryl. In certain embodiments, at least one R^(D1a) is unsubstituted aryl. In certain embodiments, at least one R^(D1a) is substituted phenyl. In certain embodiments, at least one R^(D1a) is unsubstituted phenyl. In certain embodiments, at least one R^(D1a) is substituted heteroaryl. In certain embodiments, at least one R^(D1a) is unsubstituted heteroaryl. In certain embodiments, at least one R^(D1a) is substituted pyridyl. In certain embodiments, at least one R^(D1a) is unsubstituted pyridyl. In certain embodiments, at least one R^(D1a) is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^(D1a) is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^(D1a) is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^(D1a) is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^(D1a) is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^(D1a) is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R^(D1a) groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^(D1a) groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (A), R^(D) may include a substituent R^(D2). In certain embodiments, R^(D2) is H. In certain embodiments, R^(D2) is halogen. In certain embodiments, R^(D2) is F. In certain embodiments, R^(D2) is Cl. In certain embodiments, R^(D2) is Br. In certain embodiments, R^(D2) is I (iodine). In certain embodiments, R^(D2) is substituted acyl. In certain embodiments, R^(D2) is unsubstituted acyl. In certain embodiments, R^(D2) is acetyl. In certain embodiments, R^(D2) is substituted alkyl. In certain embodiments, R^(D2) is unsubstituted alkyl. In certain embodiments, R^(D2) is C₁₋₆ alkyl. In certain embodiments, R^(D2) is methyl. In certain embodiments, R^(D2) is ethyl. In certain embodiments, R^(D2) is propyl. In certain embodiments, R^(D2) is butyl. In certain embodiments, R^(D2) is substituted alkenyl. In certain embodiments, R^(D2) is unsubstituted alkenyl. In certain embodiments, R^(D2) is substituted alkynyl. In certain embodiments, R^(D2) is unsubstituted alkynyl. In certain embodiments, R^(D2) is substituted carbocyclyl. In certain embodiments, R^(D2) is unsubstituted carbocyclyl. In certain embodiments, R^(D2) is substituted heterocyclyl. In certain embodiments, R^(D2) is unsubstituted heterocyclyl. In certain embodiments, R^(D2) is substituted aryl. In certain embodiments, R^(D2) is unsubstituted aryl. In certain embodiments, R^(D2) is substituted phenyl. In certain embodiments, R^(D2) is unsubstituted phenyl. In certain embodiments, R^(D2) is substituted heteroaryl. In certain embodiments, R^(D2) is unsubstituted heteroaryl. In certain embodiments, R^(D2) is substituted pyridyl. In certain embodiments, R^(D2) is unsubstituted pyridyl. In certain embodiments, R^(D2) is CN. In certain embodiments, R^(D2) is —NO₂. In certain embodiments, R^(D2) is —OR^(D2a). In certain embodiments, R^(D2) is —N(R^(D2a))₂. In certain embodiments, R^(D2) is —SR^(D2a). In certain embodiments, R^(D2) is —CH₂OR^(D2a). In certain embodiments, R^(D2) is —CH₂N(R^(D2a))₂. In certain embodiments, R^(D2) is —CH₂SR^(D2a).

In certain embodiments, at least one R^(D2a) is H. In certain embodiments, at least one R^(D2a) is substituted acyl. In certain embodiments, at least one R^(D2a) is unsubstituted acyl. In certain embodiments, at least one R^(D2a) is acetyl. In certain embodiments, at least one R^(D2a) is substituted alkyl. In certain embodiments, at least one R^(D2a) is unsubstituted alkyl. In certain embodiments, at least one R^(D2a) is C₁₋₆ alkyl. In certain embodiments, at least one R^(D2a) is methyl. In certain embodiments, at least one R^(D2a) is ethyl. In certain embodiments, at least one R^(D2a) is propyl. In certain embodiments, at least one R^(D2a) is butyl. In certain embodiments, at least one R^(D2a) is substituted alkenyl. In certain embodiments, at least one R^(D2a) is unsubstituted alkenyl. In certain embodiments, at least one R^(D2a) is substituted alkynyl. In certain embodiments, at least one R^(D2a) is unsubstituted alkynyl. In certain embodiments, at least one R^(D2a) is substituted carbocyclyl. In certain embodiments, at least one R^(D2a) is unsubstituted carbocyclyl. In certain embodiments, at least one R^(D2a) is substituted heterocyclyl. In certain embodiments, at least one R^(D2a) is unsubstituted heterocyclyl. In certain embodiments, at least one R^(D2a) is substituted aryl. In certain embodiments, at least one R^(D2a) is unsubstituted aryl. In certain embodiments, at least one R^(D2a) is substituted phenyl. In certain embodiments, at least one R^(D2a) is unsubstituted phenyl. In certain embodiments, at least one R^(D2a) is substituted heteroaryl. In certain embodiments, at least one R^(D2a) is unsubstituted heteroaryl. In certain embodiments, at least one R^(D2a) is substituted pyridyl. In certain embodiments, at least one R^(D2a) is unsubstituted pyridyl. In certain embodiments, at least one R^(D2a) is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^(D2a) is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^(D2a) is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^(D2a) is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^(D2a) is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^(D2a) is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R^(D2a) groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^(D2a) groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (A), R^(D) may include a substituent R^(D3). In certain embodiments, R^(D3) is H. In certain embodiments, R^(D3) is halogen. In certain embodiments, R^(D3) is F. In certain embodiments, R^(D3) is Cl. In certain embodiments, R^(D3) is Br. In certain embodiments, R^(D3) is I (iodine). In certain embodiments, R^(D3) is substituted acyl. In certain embodiments, R^(D3) is unsubstituted acyl. In certain embodiments, R^(D3) is acetyl. In certain embodiments, R^(D3) is substituted alkyl. In certain embodiments, R^(D3) is unsubstituted alkyl. In certain embodiments, R^(D3) is C₁₋₆ alkyl. In certain embodiments, R^(D3) is methyl. In certain embodiments, R^(D3) is ethyl. In certain embodiments, R^(D3) is propyl. In certain embodiments, R^(D3) is butyl. In certain embodiments, R^(D3) is substituted alkenyl. In certain embodiments, R^(D3) is unsubstituted alkenyl. In certain embodiments, R^(D3) is substituted alkynyl. In certain embodiments, R^(D3) is unsubstituted alkynyl. In certain embodiments, R^(D3) is substituted carbocyclyl. In certain embodiments, R^(D3) is unsubstituted carbocyclyl. In certain embodiments, R^(D3) is substituted heterocyclyl. In certain embodiments, R^(D3) is unsubstituted heterocyclyl. In certain embodiments, R^(D3) is substituted aryl. In certain embodiments, R^(D3) is unsubstituted aryl. In certain embodiments, R^(D3) is substituted phenyl. In certain embodiments, R^(D3) is unsubstituted phenyl. In certain embodiments, R^(D3) is substituted heteroaryl. In certain embodiments, R^(D3) is unsubstituted heteroaryl. In certain embodiments, R^(D3) is substituted pyridyl. In certain embodiments, R^(D3) is unsubstituted pyridyl. In certain embodiments, R^(D3) is —CN. In certain embodiments, R^(D3) is —NO₂. In certain embodiments, R^(D3) is —OR^(D3a). In certain embodiments, R^(D3) is —N(R^(D3a))₂. In certain embodiments, R^(D3) is —SR^(D3a). In certain embodiments, R^(D3) is —CH₂OR^(D3a). In certain embodiments, R^(D3) is —CH₂N(R^(D3a))₂. In certain embodiments, R^(D3) is —CH₂SR^(D3a).

In certain embodiments, at least one R^(D3a) is H. In certain embodiments, at least one R^(D3a) is substituted acyl. In certain embodiments, at least one R^(D3a) is unsubstituted acyl. In certain embodiments, at least one R^(D3a) is acetyl. In certain embodiments, at least one R^(D3a) is substituted alkyl. In certain embodiments, at least one R^(D3a) is unsubstituted alkyl. In certain embodiments, at least one R^(D3a) is C₁₋₆ alkyl. In certain embodiments, at least one R^(D3a) is methyl. In certain embodiments, at least one R^(D3a) is ethyl. In certain embodiments, at least one R^(D3a) is propyl. In certain embodiments, at least one R^(D3a) is butyl. In certain embodiments, at least one R^(D3a) is substituted alkenyl. In certain embodiments, at least one R^(D3a) is unsubstituted alkenyl. In certain embodiments, at least one R^(D3a) is substituted alkynyl. In certain embodiments, at least one R^(D3a) is unsubstituted alkynyl. In certain embodiments, at least one R^(D3a) is substituted carbocyclyl. In certain embodiments, at least one R^(D3a) is unsubstituted carbocyclyl. In certain embodiments, at least one R^(D3a) is substituted heterocyclyl. In certain embodiments, at least one R^(D3a) is unsubstituted heterocyclyl. In certain embodiments, at least one R^(D3a) is substituted aryl. In certain embodiments, at least one R^(D3a) is unsubstituted aryl. In certain embodiments, at least one R^(D3a) is substituted phenyl. In certain embodiments, at least one R^(D3a) is unsubstituted phenyl. In certain embodiments, at least one R^(D3a) is substituted heteroaryl. In certain embodiments, at least one R^(D3a) is unsubstituted heteroaryl. In certain embodiments, at least one R^(D3a) is substituted pyridyl. In certain embodiments, at least one R^(D3a) is unsubstituted pyridyl. In certain embodiments, at least one R^(D3a) is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^(D3a) is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^(D3a) is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^(D3a) is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^(D3a) is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^(D3a) is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R^(D3a) groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^(D3a) groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (A), R^(D) may include a substituent R^(D4). In certain embodiments, R^(D4) is a leaving group. In certain embodiments, R^(D4) is halogen. In certain embodiments, R^(D4) is F. In certain embodiments, R^(D4) is Cl. In certain embodiments, R^(D4) is Br. In certain embodiments, R^(D4) is I (iodine). In certain embodiments, R^(D4) is —OS(═O)_(w)R^(D4a). In certain embodiments, w is 1. In certain embodiments, w is 2. In certain embodiments, R^(D4) is —OMs. In certain embodiments, R^(D4) is —OTf. In certain embodiments, R^(D4) is —OTs. In certain embodiments, R^(D4) is —OBs. In certain embodiments, R^(D4) is 2-nitrobenzenesulfonyloxy. In certain embodiments, R^(D4) is —OR^(D4a). In certain embodiments, R^(D4) is —OMe. In certain embodiments, R^(D4) is —OCF₃. In certain embodiments, R^(D4) is —OPh. In certain embodiments, R^(D4) is —OC(═O)R^(D4a). In certain embodiments, R^(D4) is —OC(═O)Me. In certain embodiments, R^(D4) is —OC(═O)CF₃. In certain embodiments, R^(D4) is —OC(═O)Ph. In certain embodiments, R^(D4) is —OC(═O)Cl. In certain embodiments, R^(D4) is —OC(═O)OR^(D4a). In certain embodiments, R^(D4) is —OC(═O)OMe. In certain embodiments, R^(D4) is —OC(═O)O(t-Bu).

In certain embodiments, R^(D4a) is substituted alkyl. In certain embodiments, R^(D4a) is unsubstituted alkyl. In certain embodiments, R^(D4a) is C₁₋₆ alkyl. In certain embodiments, R^(D4a) is methyl. In certain embodiments, R^(D4a) is ethyl. In certain embodiments, R^(D4a) is propyl. In certain embodiments, R^(D4a) is butyl. In certain embodiments, R^(D4a) is substituted alkenyl. In certain embodiments, R^(D4a) is unsubstituted alkenyl. In certain embodiments, R^(D4a) is vinyl. In certain embodiments, R^(D4a) is substituted alkynyl. In certain embodiments, R^(D4a) is unsubstituted alkynyl. In certain embodiments, R^(D4a) is ethynyl. In certain embodiments, R^(D4a) is substituted carbocyclyl. In certain embodiments, R^(D4a) is unsubstituted carbocyclyl. In certain embodiments, R^(D4a) is substituted heterocyclyl. In certain embodiments, R^(D4a) is unsubstituted heterocyclyl. In certain embodiments, R^(D4a) is substituted aryl. In certain embodiments, R^(D4a) is unsubstituted aryl. In certain embodiments, R^(D4a) is substituted phenyl. In certain embodiments, R^(D4a) is unsubstituted phenyl. In certain embodiments, R^(D4a) is substituted heteroaryl. In certain embodiments, R^(D4a) is unsubstituted heteroaryl. In certain embodiments, R^(D4a) is substituted pyridyl. In certain embodiments, R^(D4a) is unsubstituted pyridyl.

In compounds of Formula (A), R^(D) may include a substituent R^(D5). In certain embodiments, R^(D5) is H. In certain embodiments, R^(D5) is substituted alkyl. In certain embodiments, R^(D5) is unsubstituted alkyl. In certain embodiments, R^(D5) is C₁₋₆ alkyl. In certain embodiments, R^(D5) is methyl. In certain embodiments, R^(D5) is ethyl. In certain embodiments, R^(D5) is propyl. In certain embodiments, R^(D5) is butyl. In certain embodiments, R^(D5) is a nitrogen protecting group. In certain embodiments, R^(D5) is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.

In certain embodiments, R^(D1) and R^(D2) are each hydrogen. In certain embodiments, R^(D1) and R^(D3) are each hydrogen. In certain embodiments, R^(D2) and R^(D3) are each hydrogen. In certain embodiments, R^(D1), R^(D2), and R^(D3) are each hydrogen. In certain embodiments, R^(D1), R^(D2), and R^(D3), and R^(D5) are each hydrogen.

In certain embodiments, a is 1. In certain embodiments, a is 2.

In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is 4. In certain embodiments, z is 5. In certain embodiments, z is 6.

In certain embodiments, Y is —O—. In certain embodiments, Y is —C(═O)—. In certain embodiments, Y is —S—. In certain embodiments, Y is —C(═S). In certain embodiments, Y is —NR^(D6)—, wherein R^(D6) is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group. In certain embodiments, Y is —NH—. In certain embodiments, Y is —NCH₃—. In certain embodiments, Y is —N(BOC)—. In certain embodiments, Y is —N(Fmoc)-. In certain embodiments, Y is —N(Cbz)—. In certain embodiments, Y is —N(Bn)-. In certain embodiments, Y is —C(═NR^(D6))—, wherein R^(D6) is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group. In certain embodiments, Y is —C(═NH)—. In certain embodiments, Y is C(═NCH₃)—. In certain embodiments, Y is —C(═NTs)-. In certain embodiments, Y is —C(═NBn)-. In certain embodiments, Y is —C(═NCH(Ph)₂)-.

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

In certain embodiments, R^(D) is of the formula:

Various combinations of certain embodiments of Formula (A) are futher contemplated herein.

For example, in certain embodiments, a compound of Formula (A) is a compound of Formula (A1) or (A2):

wherein R^(X), R^(A), R^(B), and 1 are defined herein. In certain embodiments R^(A) is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A) is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R^(B) is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R^(B) groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R^(B) group is meta to the point of attachment of the amide linker; and the second R^(B) group is para to the point of attachment of the amide linker. In certain embodiments, one R^(B) group is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, one R^(B) group is C₁₋₆alkyl substituted with one —CN group. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted —CH₂-(piperazinyl). In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is haloalkyl. In certain embodiments, one R^(B) group is —CF₃. In certain embodiments, one R^(B) group is substituted or unsubstituted imidazoyl. In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted piperazinyl. In certain embodiments, one R^(B) group is

where there alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where there alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted morpholine. In certain embodiments, two R^(B) groups are substituted or unsubstituted morpholine. In certain embodiments, R^(X) is —N(R^(A1))N(R^(A1))₂. In certain embodiments, R^(X) is —N(R^(A1))N(R^(A1))₂; and each instance of R^(A) is hydrogen, methyl, or acetyl. In certain embodiments, R^(X) is —NHNMe₂ or —NHNHAc. In certain embodiments, R^(X) is —NH₂. In certain embodiments, R^(X) is —NH(R^(A1)). In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is substituted or unsubstituted methyl. In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is acyl. In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is substituted or unsubstituted —C(═O)—(C₁₋₆alkyl). In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is acetyl or propionyl. In certain embodiments, R^(X) is NH(R^(A1)); and R^(A1) is substituted or unsubstituted —C(═O)-(carbocyclyl). In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is substituted or unsubstituted —C(═O)-(cyclopropyl). In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is substituted or unsubstituted heteroaryl. In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is substituted or unsubstituted pyrazole. In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is substituted or unsubstituted isoxazole. In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is substituted or unsubstituted pyrimidine. In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is substituted or unsubstituted heterocyclyl. In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is substituted or unsubstituted azetidine. In certain embodiments, R^(X) is —NH(R^(A1)); and R^(A1) is substituted or unsubstituted oxetane.

In certain embodiments, a compound of Formula (A1) is a compound of Formula (A1-a), (A1-b), (A1-c), or (A1-d):

wherein R^(Xa), R^(Xc), R^(A), R^(B), and 1 are defined herein. In certain embodiments R^(A) is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A) is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R^(B) is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R^(B) groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R^(B) group is meta to the point of attachment of the amide linker; and the second R^(B) group is para to the point of attachment of the amide linker. In certain embodiments, one R^(B) group is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, one R^(B) group is C₁₋₆alkyl substituted with one —CN group. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted —CH₂-(piperazinyl). In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is haloalkyl. In certain embodiments, one R^(B) group is —CF₃. In certain embodiments, one R^(B) group is substituted or unsubstituted imidazoyl. In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted piperazinyl. In certain embodiments, one R^(B) group is

where there alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where there alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted morpholine. In certain embodiments, two R^(B) groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R^(Xc) are hydrogen. In certain embodiments, R^(Xa) is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, R^(Xa) is methyl or ethyl.

In certain embodiments, a compound of Formula (A2) is a compound of Formula (A2-a), (A2-b), (A2-c), or (A2-d):

wherein R^(Xa), R^(Xc), R^(A), R^(B), are 1 are defined herein. In certain embodiments R^(A) is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A) is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R^(B) is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R^(B) groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R^(B) group is meta to the point of attachment of the amide linker; and the second R^(B) group is para to the point of attachment of the amide linker. In certain embodiments, one R^(B) group is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, one R^(B) group is C₁₋₆alkyl substituted with one —CN group. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted —CH₂-(piperazinyl). In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) is

In certain embodiments, one R^(B) group is haloalkyl. In certain embodiments, one R^(B) group is —CF₃. In certain embodiments, one R^(B) group is substituted or unsubstituted imidazoyl. In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted piperazinyl. In certain embodiments, one R^(B) group is

where there alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where there alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted morpholine. In certain embodiments, two R^(B) groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R^(Xc) are hydrogen. In certain embodiments, R^(Xa) is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, R^(Xa) is methyl or ethyl.

In certain embodiments, a compound of Formula (A1) is a compound of Formula (A1-e)-(A1-p):

wherein R^(Xa), R^(Xc), R^(A), and R^(B) are defined herein. In certain embodiments R^(A) is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A) is methyl. In certain embodiments, one R^(B) group is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, one R^(B) group is C₁₋₆alkyl substituted with one —CN group. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted —CH₂-(piperazinyl). In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is haloalkyl. In certain embodiments, one R^(B) group is —CF₃. In certain embodiments, one R^(B) group is substituted or unsubstituted imidazoyl. In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted piperazinyl. In certain embodiments, one R^(B) group is

where there alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where there alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted morpholine. In certain embodiments, two R^(B) groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R^(Xc) are hydrogen. In certain embodiments, R^(Xa) is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, R^(Xa) is methyl or ethyl.

In certain embodiments, a compound of Formula (A2) is a compound of Formula (A2-e)-(A2-p):

wherein R^(Xa), R^(Xc), R^(A), and R^(B) are defined herein. In certain embodiments R^(A) is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A) is methyl. In certain embodiments, one R^(B) group is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, one R^(B) group is C₁₋₆alkyl substituted with one —CN group. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted —CH₂-(piperazinyl). In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is haloalkyl. In certain embodiments, one R^(B) group is CF₃. In certain embodiments, one R^(B) group is substituted or unsubstituted imidazoyl. In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted piperazinyl. In certain embodiments, one R^(B) group is

where there alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where there alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted morpholine. In certain embodiments, two R^(B) groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R^(Xc) are hydrogen. In certain embodiments, R^(Xa) is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, R^(Xa) is methyl or ethyl.

In certain embodiments, a compound of Formula (A) is a compound of Formula (A3) or (A4):

wherein R^(D), R^(A), R^(B), and 1 are defined herein. In certain embodiments R^(A) is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A) is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R^(B) is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R^(B) groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R^(B) group is meta to the point of attachment of the amide linker; and the second R^(B) group is para to the point of attachment of the amide linker. In certain embodiments, one R^(B) group is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, one R^(B) group is C₁₋₆alkyl substituted with one —CN group. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted —CH₂-(piperazinyl). In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is haloalkyl. In certain embodiments, one R^(B) group is —CF₃. In certain embodiments, one R^(B) group is substituted or unsubstituted imidazoyl. In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted piperazinyl. In certain embodiments, one R^(B) group is

where there alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where there alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted morpholine. In certain embodiments, two R^(B) groups are substituted or unsubstituted morpholine. In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, a compound of Formula (A3) is a compound of Formula (A3-a), (A3-b), or (A3-c):

wherein R^(D), R^(A), R^(B), and 1 are defined herein. In certain embodiments R^(A) is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A) is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R^(B) is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R^(B) groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R^(B) group is meta to the point of attachment of the amide linker; and the second R^(B) group is para to the point of attachment of the amide linker. In certain embodiments, one R^(B) group is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, one R^(B) group is C₁₋₆alkyl substituted with one —CN group. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted —CH₂-(piperazinyl). In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is haloalkyl. In certain embodiments, one R^(B) group is —CF₃. In certain embodiments, one R^(B) group is substituted or unsubstituted imidazoyl. In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted piperazinyl. In certain embodiments, one R^(B) group is

where there alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where there alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted morpholine. In certain embodiments, two R^(B) groups are substituted or unsubstituted morpholine. In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, a compound of Formula (A4) is a compound of Formula (A4-a), (A4-b), or (A4-c):

wherein R^(D), R^(A), R^(B), and 1 are defined herein. In certain embodiments R^(A) is substituted or unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A) is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R^(B) is meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R^(B) groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R^(B) group is meta to the point of attachment of the amide linker; and the second R^(B) group is para to the point of attachment of the amide linker. In certain embodiments, one R^(B) group is substituted or unsubstituted C₁₋₆alkyl. In certain embodiments, one R^(B) group is C₁₋₆alkyl substituted with one —CN group. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted —CH₂-(piperazinyl). In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is haloalkyl. In certain embodiments, one R^(B) group is —CF₃. In certain embodiments, one R^(B) group is substituted or unsubstituted imidazoyl. In certain embodiments, one R^(B) group is

where the alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where the alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted piperazinyl. In certain embodiments, one R^(B) group is

where there alkyl is optionally substituted. In certain embodiments, one R^(B) group is

where there alkyl is unsubstituted. In certain embodiments, one R^(B) group is

In certain embodiments, one R^(B) group is substituted or unsubstituted morpholine. In certain embodiments, two R^(B) groups are substituted or unsubstituted morpholine. In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

Another aspect of the invention relates to the compound of Formula (I-11):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

In another aspect, provided are compounds of Formula (V):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof; wherein:

each instance of each instance of R^(A)′, R^(B)′, and R^(X)′ are independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR^(A1)′, —N(R^(A1)′)₂, —SR^(A1)′, —CN, —C(═O)R^(A1)′, —C(═O)^(A1)′, —C(═O)SR^(A1)′, —C(═O)N(R^(A1)′)₂, —C(═S(R^(A1)′, —C(═S)OR^(A1)′, —C(═S)SR^(A1)′, —C(═S)N(R^(A1)′)₂, —C(═NR^(A1)′)R^(A1)′, —C(═NR^(A1)′)OR^(A1)′, —C(═NR^(A1)′)SR^(A1)′, —C(═NR^(A1)′)N(R^(A1)′)₂, —NO₂, —N₃, —N(R^(A1)′)₃ ⁺X′⁻, wherein X′⁻, wherein X′⁻ is a counterion, —N(OR^(A1)′)R^(A1)′, —NR^(A1)′C(═O)R^(A1)′, —NR^(A1)′C(═O)OR^(A1)′, —NR^(A1)′C(═O)SR^(A1)′, —NR^(A1)′C(═O)N(R^(A1)′)₂, —NR^(A1)′C(═S)R^(A1)′, —NR^(A1)′C(═S)OR^(A1)′, —NR^(A1)′C(═S)SR^(A1)′, —NR^(A1)′C(═S)N(R^(A1)′)₂, —NR^(A1)′C(═NR^(A1)′)R^(A1)′, —NR^(A1)′C(═NR^(A1)′)OR^(A1)′, —NR^(A1)′C(═NR^(A1)′)SR^(A1)′, —NR^(A1)′C(═NR^(A1)′)N(R^(A1)′)₂, —NR^(A1)′S(═O)₂R^(A1)′, —NR^(A1)′S(═O)₂OR^(A1)′, —NR^(A1)′S(═O)₂SR^(A1)′, —NR^(A1)′S(═O)₂N(R^(A1)′)₂, —NR^(A1)′S(═O)R^(A1)′, —NR^(A1)′S(═O)OR^(A1)′, —NR^(A1)′S(═O)SR^(A1)′, —NR^(A1)′S(═O)N(R^(A1)′)₂, —NR^(A1)′P(═O), —NR^(A1)′P(═O)₂—NR^(A1)′P(═O(R^(A1)′)₂, —NR^(A1)′P(═O)R^(A1)′(OR^(A1)′), —NR^(A1)′P(═O)(OR^(A1)′)₂, —OC(═O)R^(A1)′, —OC(═O)OR^(A1)′, —OC(═O)SR^(A1)′, —OC(═O)N(R^(A1)′)₂, —OC(═NR^(A1)′)R^(A1)′, —OC(═NR^(A1)′)OR^(A1)′, —OC(═NR^(A1)′)N(R^(A1)′)₂, —OC(═S)R^(A1)′, —OC(═S)OR^(A1)′, —OC(═S)SR^(A1)′, —OC(═S)N(R^(A1)′)₂, —ON(R^(A1)′)₂, —OC(═O)R^(A1)′, —OS(═O)OR^(A1)′, —OS(═O)SR^(A1)′, —OS(═O)N(R^(A1)′)₂, —OS(═O)₂R^(A1)′, —OS(═O)₂OR^(A1)′, —OS(═O)₂SR^(A1)′, —OS(═O)₂N(R^(A1)′)₂, —OP(═O)₂, —OP(═O)(R^(A1)′)₂, —OP(═O)R^(A1)′(OR^(A1)′), —OP(═O)(OR^(A1)′)₂, —OP(═O), —OP(R^(A1)′)₂, —OPR^(A1)′(OR^(A1)′), —OP(OR^(A1)′)₂, —OSi(R^(A1)′)₃, —OSi(R^(A1)′)₂OR^(A1)′, —OSi(R^(A1)′)(OR^(A1)′)₂, —OSi(OR^(A1)′)₃, —SSR^(A1)′, —S(═O)R^(A1)′, —S(═O)OR^(A1)′, —S(═O)N(R^(A1)′)₂, —S(═O)₂R^(A1)′, —S(═O)₂OR^(A1)′, —S(═O)₂N(R^(A1)′)₂, —SC(═O)R^(A1)′, —SC(═O)OR^(A1)′, —SC(═O)SR^(A1)′, —SC(═O)N(R^(A1)′)₂, —SC(═S)R^(A1)′, —SC(═S)OR^(A1)′, —SC(═S)SR^(A1)′, —SC(═S)N(R^(A1)′)₂, —P(R^(A1)′)₂, —PR^(A1)′(OR^(A1)′), —P(OR^(A1)′), —P(═O), —P(═O)(R^(A1)′)₂, —P(═O)(OR^(A1)′)₂, —P(═O)R^(A1)′(OR^(A1)′), —P(═O)₂, —B(R^(A1)′)₂, —B(OR^(A1)′)₂, —BR^(A1)′(OR^(A1)′), —Si(R^(A1)′)₃, —Si(R^(A1)′)₂OR^(A1)′, —SiR^(A1)′(OR^(A1)′)₂, and —Si(OR^(A1)′)₃, two R^(A)′ or R^(B)′ groups are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring, or R^(A)′ or R^(B)′ forms an optional 5 to 8 membered ring with any one of X′, Y′, Z′, Q′, U′, or Cy; wherein each occurrence of R^(A1)′ is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R^(A1)′ groups are joined to form an optionally substituted heterocyclic ring;

k′ and l′ are each independently 0, 1, 2, 3, 4, or 5;

X′, Y′, Z′ are each independently —CH₂, —CHR^(A)′, —CH, —C(R^(A)′)₂, —C, —N, —NR^(A)′, —O, —S or —C═O, or bond and may optionally form a 5 to 8 membered ring with R^(A)′ or R^(B)′;

Q′ and U′ are each independently —NR^(A)′, —O, —C═O, —NR^(A)′CO, or bond;

Ring A′ is an optionally substituted aryl, or optionally substituted heteroaryl ring

Ring C′ is an optionally substituted aryl ring; and

Cy is an optionally substituted aryl ring, optionally substituted heteroaryl ring, bond, or hydrogen.

Compounds of Formula (V) include an aryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is naphthyl, the invention provides compounds of Formula (V-a):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an aryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, Ring A′ is naphthyl, the invention provides compounds of Formula (V-b):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an aryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is phenyl, the invention provides compounds of Formula (V-c):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an aryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is phenyl, the invention provides compounds of Formula (V-d):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is pyrrolopyrimidine, the invention provides compounds of Formula (V-e):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is a pyrimidine, the invention provides compounds of Formula (V-e^(A)):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is a 1H-pyrazolo[3,4-d]pyrimidin-4-amine, the invention provides compounds of Formula (V-e^(B)):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is a furo[2,3-c]pyridin-7-amine, the invention provides compounds of Formula (V-e^(C)):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is a quinazoline, the invention provides compounds of Formula (V-e^(D)):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is phenyl, and at least one R^(A)′ group links to Cy forming an optional 5 to 8 membered ring, the invention provides compounds of Formula (V-f):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is phenyl, and at least one R^(A)′ group links to Cy forming an optional 5 to 8 membered ring, the invention provides compounds of Formula (V-g):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, k′, and l′ are as defined herein.

In another aspect, provided herein are compounds of Formula (II):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof; wherein:

each instance of R^(D)′ is independently an optional electrophilic moiety that can be attached to Cy, Ring A′, or Ring C′;

each instance of m′ is independently 0 or 1; and

Ring A′, Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, k′, and l′ are as defined herein.

In certain embodiments, R^(D)′ is an optional electrophilic moiety that can be attached to Cy, Ring A′, or Ring C′; and m′ is 0 or 1. In compounds of Formula (II), R^(D)′ is an optional electrophilic moiety that can be attached to Cy, Ring A′, or Ring C′. In certain embodiments, R^(D)′ is any one of Formulae (i-1)-(i-17):

wherein:

R^(D1)′ is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^(D1a)′, —N(R^(D1a))₂, —SR^(D1a), —CH₂OR^(D1a)′, —CH₂N(R^(D1a)′)₂, —CH₂SR^(D1a)′, —C(═O)R^(D1a)′, —C(═O)OR^(D1a)′, —C(═O)SR^(D1a)′, —C(═O)N(R^(D1a)′)₂, —C(═S)R^(D1a)′, —C(═S)OR^(D1a)′, —C(═S)SR^(D1a)′, —C(═S)N(R^(D1a)′)₂, —C(═NR^(D1a)′)R^(D1a)′, —C(═NR^(D1a)′)OR^(D1a)′, —C(═NR^(D1a)′)SR^(D1a)′, and —C(═NR^(D1a)′)_(N)(R^(D1a)′)₂, wherein each occurence of R^(D1a)′ is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^(D1a)′ groups are joined to form an optionally substituted heterocyclic ring;

R^(D2)′ is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^(D2a)′, —N(R^(D2af))₂, —SR^(D2a)′, —CH₂OR^(D2a)′, —CH₂N(R^(D2a)′)₂, —CH₂SR^(D2a)′, —C(═O)R^(D2a)′, —C(═O)OR^(D2a)′, —C(═O)SR^(D2a)′, —C(═O)N(R^(D2a)′)₂, —C(═S)R^(D2a)′, —C(═S)OR^(D2a)′, —C(═S)SR^(D2a), —C(═S)N(R^(D2a)′)₂, —C(═NR^(D2a)′)R^(D2a)′, —C(═NR^(D2a)′)OR^(D2a)′, —C(═NR^(D2a)′)SR^(D2a)′, and —C(═NR^(D2a)′)N(R^(D2a)′)₂, wherein each occurrence of R^(D2a)′ is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^(D2a)′ groups are joined to form an optionally substituted heterocyclic ring;

R^(D3)′ is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^(D3a)′, —N(R^(D3a)′)₂, —SR^(D3a)′, —CH₂OR^(D3a)′, —CH₂N(R^(D3a)′)₂, —CH₂SR^(D3a)′, —C(═O)R^(D3a), —C(═O)OR^(D3a)′, —C(═O)SR^(D3a)′, —C(═O)N(R^(D3a)′)₂, —C(═S)R^(D3a)′, —C(═S)OR^(D3a)′, —C(═S)SR^(D3a)′, —C(═S)N(R^(D3a)′)₂, —C(═NR^(D3af)′)R^(D3a)′, —C(═NR^(D3a)′)OR^(D3a)′, —C(═NR^(D3af)′)SR^(D3a)′, and —C(═NR^(D3a)′)N(R^(D3a)′)₂, wherein each occurrence of R^(D3a)′ is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^(D3a)′ groups are joined to form an optionally substituted heterocyclic ring;

optionally R^(D1)′ and R^(D3)′, or R^(D2)′ and R^(D3)′, or R^(D1)′ and R^(D2)′ are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

R^(D4)′ is a leaving group;

R^(D5)′ is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group;

Y^(Z)′ is —O, —S, or —NR^(D6)′, wherein R^(D6)′ is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group;

a′ is 1 or 2; and

z′ is 0, 1, 2, 3, 4, 5, or 6.

Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is naphthyl, the invention provides compounds of Formula (II-a):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(D)′, R^(X)′, k′, l′, and m′ are as defined herein.

Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is naphthyl, the invention provides compounds of Formula (II-b):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(D)′, R^(X)′, k′, l′, and m′ are as defined herein.

Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is phenyl, the invention provides compounds of Formula (II-c):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(D)′, R^(X)′, k′, l′, and m′ are as defined herein.

Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is phenyl, the invention provides compounds of Formula (II-d):

wherein Ring C′, Cy, Q′, U′, X′, Y^(′), Z^(′), R^(D)′, R^(X)′, k^(′), l′, and m′ are as defined herein.

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is pyrrolopyrimidine, the invention provides compounds of Formula (II-e):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(D)′, R^(X)′, k′, l′, and m′ are as defined herein.

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is pyrimidine, the invention provides compounds of Formula (II-e^(A)):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(D)′, R^(X)′, k′, l′, and m′ are as defined herein.

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is pyrimidine, the invention provides compounds of Formula (II-e^(B)):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(D)′, R^(X)′, k′, l′, and m′ are as defined herein.

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is a furo[2,3-c]pyridin-7-amine, the invention provides compounds of Formula (II-e^(C)):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is a quinazoline, the invention provides compounds of Formula (II-e^(D)):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(X)′, k′, and l′ are as defined herein.

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is phenyl, and at least one R^(A)′ group links to Cy forming an optional 5 to 8 membered ring, the invention provides compounds of Formula (II-f):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R^(A)′, R^(B)′, R^(D)′, R^(X)′, k′, l′, and m′ are as defined herein.

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, when Ring A′ is phenyl, and at least one R^(A)′ group links to Cy forming an optional 5 to 8 membered ring, the invention provides compounds of Formula (II-g):

wherein Ring C′, Cy, Q′, U′, X′, Y^(′), Z^(′), R^(D)′, R^(X)′, k′, l′, and m′ are as defined herein.

In compounds of Formula (II), R^(D)′ is a substituent on Ring A′, Ring C′, or Cy. In certain embodiments, R^(D)′ comprises a Michael acceptor moiety. This Michael acceptor moiety may react with a cysteine or other nucleophilic residue to allow covalent attachment of the compound to the target. In certain embodiments, the covalent attachment is irreversible. In other embodiments, the covalent attachment is reversible. In certain embodiments, R^(D)′ is of Formula (i-1). In certain embodiments, R^(D)′ is of Formula (i-2). In certain embodiments, R^(D)′ is of Formula (i-3). In certain embodiments, R^(D)′ is of Formula (i-4). In certain embodiments, R^(D)′ is of Formula (i-5). In certain embodiments, R^(D)′ is of Formula (i-6). In certain embodiments, R^(D)′ is of Formula (i-7). In certain embodiments, R^(D)′ is of Formula (i-8). In certain embodiments, R^(D)′ is of Formula (i-9). In certain embodiments, R^(D)′ is of Formula (i-10). In certain embodiments, R^(D)′ is of Formula (i-11). In certain embodiments, R^(D)′ is of Formula (i-12). In certain embodiments, R^(D)′ is of Formula (i-13). In certain embodiments, R^(D)′ is of Formula (i-14). In certain embodiments, R^(D)′ is of Formula (i-15). In certain embodiments, R^(D)′ is of Formula (i-16). In certain embodiments, R^(D)′ is of Formula (i-17).

In compounds of Formula (II), R^(D)′ may include a substituent R^(D1)′. In certain embodiments, R^(D1)′ is H. In certain embodiments, R^(D1)′ is halogen. In certain embodiments, R^(D1)′ is F. In certain embodiments, R^(D1)′ is Cl. In certain embodiments, R^(D1)′ is Br. In certain embodiments, R^(D1)′ is I (iodine). In certain embodiments, R^(D1)′ is substituted acyl. In certain embodiments, R^(D1)′ is unsubstituted acyl. In certain embodiments, R^(D1)′ is acetyl. In certain embodiments, R^(D1)′ is substituted alkyl. In certain embodiments, R^(D1)′ is unsubstituted alkyl. In certain embodiments, R^(D1)′ is C₁₋₆ alkyl. In certain embodiments, R^(D1)′ is methyl. In certain embodiments, R^(D1)′ is ethyl. In certain embodiments, R^(D1)′ is propyl. In certain embodiments, R^(D1)′ is butyl. In certain embodiments, R^(D1)′ is substituted alkenyl. In certain embodiments, R^(D1)′ is unsubstituted alkenyl. In certain embodiments, R^(D1)′ is substituted alkynyl. In certain embodiments, R^(D1)′ is unsubstituted alkynyl. In certain embodiments, R^(D1)′ is substituted carbocyclyl. In certain embodiments, R^(D1)′ is unsubstituted carbocyclyl. In certain embodiments, R^(D1)′ is substituted heterocyclyl. In certain embodiments, R^(D1)′ is unsubstituted heterocyclyl. In certain embodiments, R^(D1)′ is substituted aryl. In certain embodiments, R^(D1)′ is unsubstituted aryl. In certain embodiments, R^(D1)′ is substituted phenyl. In certain embodiments, R^(D1)′ is unsubstituted phenyl. In certain embodiments, R^(D1)′ is substituted heteroaryl. In certain embodiments, R^(D1)′ is unsubstituted heteroaryl. In certain embodiments, R^(D1)′ is substituted pyridyl. In certain embodiments, R^(D1)′ is unsubstituted pyridyl. In certain embodiments, R^(D1)′ is —CN. In certain embodiments, R^(D1)′ is —NO₂. In certain embodiments, R^(D1)′ is —OR^(D1a)′. In certain embodiments, R^(D1)′, is —N(R^(D1a)′)₂. In certain embodiments, R^(D1)′ is —SR^(D1a)′. In certain embodiments, R^(D1)′ is —CH₂OR^(D1a)′. In certain embodiments, R^(D1)′ is —CH₂N(R^(D1a)′)₂. In certain embodiments, R^(D1)′ is —CH₂SR^(D1a)′.

In certain embodiments, at least one R^(D1a)′ is H. In certain embodiments, at least one R^(D1a)′ is substituted acyl. In certain embodiments, at least one R^(D1a)′ is unsubstituted acyl. In certain embodiments, at least one R^(D1a)′ is acetyl. In certain embodiments, at least one R^(D1a)′ is substituted alkyl. In certain embodiments, at least one R^(D1a)′ is unsubstituted alkyl. In certain embodiments, at least one R^(D1a)′ is C₁₋₆ alkyl. In certain embodiments, at least one R^(D1a)′ is methyl. In certain embodiments, at least one R^(D1a)′ is ethyl. In certain embodiments, at least one R^(D1a)′ is propyl. In certain embodiments, at least one R^(D1a)′ is butyl. In certain embodiments, at least one R^(D1a)′ is substituted alkenyl. In certain embodiments, at least one R^(D1a)′ is unsubstituted alkenyl. In certain embodiments, at least one R^(D1a)′ is substituted alkynyl. In certain embodiments, at least one R^(D1a)′ is unsubstituted alkynyl. In certain embodiments, at least one R^(D1)′ is substituted carbocyclyl. In certain embodiments, at least one R^(D1a)′ is unsubstituted carbocyclyl. In certain embodiments, at least one R^(D1a)′ is substituted heterocyclyl. In certain embodiments, at least one R^(D1a)′ is unsubstituted heterocyclyl. In certain embodiments, at least one R^(D1a)′ is substituted aryl. In certain embodiments, at least one R^(D1a)′ is unsubstituted aryl. In certain embodiments, at least one R^(D1a)′ is substituted phenyl. In certain embodiments, at least one R^(D1a)′ is unsubstituted phenyl. In certain embodiments, at least one R^(D1a)′ is substituted heteroaryl. In certain embodiments, at least one R^(D1a)′ is unsubstituted heteroaryl. In certain embodiments, at least one R^(D1a)′ is substituted pyridyl. In certain embodiments, at least one R^(D1a)′ is unsubstituted pyridyl. In certain embodiments, at least one R^(D1a)′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^(D1a)′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^(D1a)′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^(D1a)′ is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^(D1a)′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^(D1a)′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R^(D1a)′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^(D1a)′ groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (II), R^(D)′ may include a substituent R^(D2)′. In certain embodiments, R^(D2)′ is H. In certain embodiments, R^(D2)′ is halogen. In certain embodiments, R^(D2)′ is F. In certain embodiments, R^(D2)′ is Cl. In certain embodiments, R^(D2)′ is Br. In certain embodiments, R^(D2)′ is I (iodine). In certain embodiments, R^(D2)′ is substituted acyl. In certain embodiments, R^(D2)′ is unsubstituted acyl. In certain embodiments, R^(D2)′ is acetyl. In certain embodiments, R^(D2)′ is substituted alkyl. In certain embodiments, R^(D2)′ is unsubstituted alkyl. In certain embodiments, R^(D2)′ is C₁₋₆ alkyl. In certain embodiments, R^(D2)′ is methyl. In certain embodiments, R^(D2)′ is ethyl. In certain embodiments, R^(D2)′ is propyl. In certain embodiments, R^(D2)′ is butyl. In certain embodiments, R^(D2)′ is substituted alkenyl. In certain embodiments, R^(D2)′ is unsubstituted alkenyl. In certain embodiments, R^(D2)′ is substituted alkynyl. In certain embodiments, R^(D2)′ is unsubstituted alkynyl. In certain embodiments, R^(D2)′ is substituted carbocyclyl. In certain embodiments, R^(D2)′ is unsubstituted carbocyclyl. In certain embodiments, R^(D2)′ is substituted heterocyclyl. In certain embodiments, R^(D2)′ is unsubstituted heterocyclyl. In certain embodiments, R^(D2)′ is substituted aryl. In certain embodiments, R^(D2)′ is unsubstituted aryl. In certain embodiments, R^(D2)′ is substituted phenyl. In certain embodiments, R^(D2)′ is unsubstituted phenyl. In certain embodiments, R^(D2)′ is substituted heteroaryl. In certain embodiments, R^(D2)′ is unsubstituted heteroaryl. In certain embodiments, R^(D2)′ is substituted pyridyl. In certain embodiments, R^(D2)′ is unsubstituted pyridyl. In certain embodiments, R^(D2)′ is —CN. In certain embodiments, R^(D2)′ is —NO₂. In certain embodiments, R^(D2)′ is —OR^(D2a)′. In certain embodiments, R^(D2)′ is —N(R^(D2a)′)₂. In certain embodiments, R^(D2)′ is —SR^(D2a)′. In certain embodiments, R^(D2)′ is —CH₂OR^(D2a)′. In certain embodiments, R^(D2), —CH₂N(R^(D2a)′)₂. In certain embodiments, R^(D2)′ is —CH₂SR^(D2)′.

In certain embodiments, at least one R^(D2a)′ is H. In certain embodiments, at least one R^(D2a)′ is substituted acyl. In certain embodiments, at least one R^(D2a)′ is unsubstituted acyl. In certain embodiments, at least one R^(D2a′) is acetyl. In certain embodiments, at least one R^(D2a)′ is substituted alkyl. In certain embodiments, at least one R^(D2a)′ is unsubstituted alkyl. In certain embodiments, at least one R^(D2a′) is C₁₋₆ alkyl. In certain embodiments, at least one R^(D2a)′ is methyl. In certain embodiments, at least one R^(D2a′) is ethyl. In certain embodiments, at least one R^(D2a)′ is propyl. In certain embodiments, at least one R^(D2a)′ is butyl. In certain embodiments, at least one R^(D2a)′ is substituted alkenyl. In certain embodiments, at least one R^(D2a)′ is unsubstituted alkenyl. In certain embodiments, at least one R^(D2a)′ is substituted alkynyl. In certain embodiments, at least one R^(D2a)′ is unsubstituted alkynyl. In certain embodiments, at least one R^(D2a)′ is substituted carbocyclyl. In certain embodiments, at least one R^(D2a)′ is unsubstituted carbocyclyl. In certain embodiments, at least one R^(D2a)′ is substituted heterocyclyl. In certain embodiments, at least one R^(D2a)′ is unsubstituted heterocyclyl. In certain embodiments, at least one R^(D2a)′ is substituted aryl. In certain embodiments, at least one R^(D2a)′ is unsubstituted aryl. In certain embodiments, at least one R^(D2a)′ is substituted phenyl. In certain embodiments, at least one R^(D2a)′ is unsubstituted phenyl. In certain embodiments, at least one R^(D2a)′ is substituted heteroaryl. In certain embodiments, at least one R^(D2a)′ is unsubstituted heteroaryl. In certain embodiments, at least one R^(D2a)′ is substituted pyridyl. In certain embodiments, at least one R^(D2a)′ is unsubstituted pyridyl. In certain embodiments, at least one R^(D2a)′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^(D2a)′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^(D2a)′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^(D2a)′ is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^(D2a)′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^(D2a)′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R^(D2a)′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^(D2a)′ groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (II), R^(D)′ may include a substituent R^(D3)′. In certain embodiments, R^(D3)′ is H. In certain embodiments, R^(D3)′ is halogen. In certain embodiments, R^(D3)′ is F. In certain embodiments, R^(D3)′ is Cl. In certain embodiments, R^(D3)′ is Br. In certain embodiments, R^(D3)′ is I (iodine). In certain embodiments, R^(D3)′ is substituted acyl. In certain embodiments, R^(D3)′ is unsubstituted acyl. In certain embodiments, R^(D3)′ is acetyl. In certain embodiments, R^(D3)′ is substituted alkyl. In certain embodiments, R^(D3)′ is unsubstituted alkyl. In certain embodiments, R^(D3)′ is C₁₋₆ alkyl. In certain embodiments, R^(D3)′ is methyl. In certain embodiments, R^(D3)′ is ethyl. In certain embodiments, R^(D3)′ is propyl. In certain embodiments, R^(D3)′ is butyl. In certain embodiments, R^(D3)′ is substituted alkenyl. In certain embodiments, R^(D3)′ is unsubstituted alkenyl. In certain embodiments, R^(D3)′ is substituted alkynyl. In certain embodiments, R^(D3)′ is unsubstituted alkynyl. In certain embodiments, R^(D3)′ is substituted carbocyclyl. In certain embodiments, R^(D3)′ is unsubstituted carbocyclyl. In certain embodiments, R^(D3)′ is substituted heterocyclyl. In certain embodiments, R^(D3)′ is unsubstituted heterocyclyl. In certain embodiments, R^(D3)′ is substituted aryl. In certain embodiments, R^(D3)′ is unsubstituted aryl. In certain embodiments, R^(D3)′ is substituted phenyl. In certain embodiments, R^(D3)′ is unsubstituted phenyl. In certain embodiments, R^(D3)′ is substituted heteroaryl. In certain embodiments, R^(D3)′ is unsubstituted heteroaryl. In certain embodiments, R^(D3)′ is substituted pyridyl. In certain embodiments, R^(D3)′ is unsubstituted pyridyl. In certain embodiments, R^(D3)′ is —CN. In certain embodiments, R^(D3)′ is —NO₂. In certain embodiments, R^(D3)′ is —OR^(D3)′. In certain embodiments, R^(D3)′ is —N(R^(D3a)′)₂. In certain embodiments, R^(D3)′ is —SR^(D3a)′. In certain embodiments, R^(D3)′ is —CH₂OR^(D3a)′. In certain embodiments, R^(D3)′ is —CH₂N(R^(D3a)′)₂. In certain embodiments, R^(D3)′ is —CH₂SR^(D3a)′.

In certain embodiments, at least one R^(D3a)′ is H. In certain embodiments, at least one R^(D3a)′ is substituted acyl. In certain embodiments, at least one R^(D3a)′ is unsubstituted acyl. In certain embodiments, at least one R^(D3a)′ is acetyl. In certain embodiments, at least one R^(D3a)′ is substituted alkyl. In certain embodiments, at least one R^(D3a)′ is unsubstituted alkyl. In certain embodiments, at least one R^(D3a)′ is C₁₋₆ alkyl. In certain embodiments, at least one R^(D3a)′ is methyl. In certain embodiments, at least one R^(D3a)′ is ethyl. In certain embodiments, at least one R^(D3a)′ is propyl. In certain embodiments, at least one R^(D3a)′ is butyl. In certain embodiments, at least one R^(D3a)′ is substituted alkenyl. In certain embodiments, at least one R^(D3a)′ is unsubstituted alkenyl. In certain embodiments, at least one R^(D3a)′ is substituted alkynyl. In certain embodiments, at least one R^(D3a)′ is unsubstituted alkynyl. In certain embodiments, at least one R^(D3a)′ is substituted carbocyclyl. In certain embodiments, at least one R^(D3a)′ is unsubstituted carbocyclyl. In certain embodiments, at least one R^(D3a)′ is substituted heterocyclyl. In certain embodiments, at least one R^(D3a)′ is unsubstituted heterocyclyl. In certain embodiments, at least one R^(D3a)′ is substituted aryl. In certain embodiments, at least one R^(D3a)′ is unsubstituted aryl. In certain embodiments, at least one R^(D3a)′ is substituted phenyl. In certain embodiments, at least one R^(D3a)′ is unsubstituted phenyl. In certain embodiments, at least one R^(D3a)′ is substituted heteroaryl. In certain embodiments, at least one R^(D3a)′ is unsubstituted heteroaryl. In certain embodiments, at least one R^(D3a)′ is substituted pyridyl. In certain embodiments, at least one R^(D3a)′ is unsubstituted pyridyl. In certain embodiments, at least one R^(D3a)′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^(D3a)′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^(D3a)′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^(D3a)′ is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^(D3a)′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^(D3a)′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.

In certain embodiments, two R^(D3a)′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^(D3a)′ groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (II), R^(D)′ may include a substituent R^(D4)′. In certain embodiments, R^(D4)′ is a leaving group. In certain embodiments, R^(D4)′ is halogen. In certain embodiments, R^(D4)′ is F. In certain embodiments, R^(D4)′ is Cl. In certain embodiments, R^(D4)′ is Br. In certain embodiments, R^(D4)′ is I (iodine). In certain embodiments, R^(D4)′ is —OS(═O)_(w′)R^(D4a)′. In certain embodiments, w′ is 1. In certain embodiments, w′ is 2. In certain embodiments, R^(D4)′ is OMs. In certain embodiments, R^(D4)′ is —OTf. In certain embodiments, R^(D4)′ is —OTs. In certain embodiments, R^(D4)′ is —OBs. In certain embodiments, R^(D4)′ is 2-nitrobenzenesulfonyloxy. In certain embodiments, R^(D4), is —OR^(D4a). In certain embodiments, R^(D4)′ is —OMe. In certain embodiments, R^(D4)′ is —OCF₃. In certain embodiments, R^(D4)′ is —OPh. In certain embodiments, R^(D4)′is —OC(═O)R^(D4a)′. In certain embodiments, R^(D4)′ is —OC(═O)Me. In certain embodiments, R^(D4)′ is —OC(═O)CF₃. In certain embodiments, R^(D4)′ is —OC(═O)Ph. In certain embodiments, R^(D4)′ is —OC(═O)Cl. In certain embodiments, R^(D4)′ is —OC(═O)OR^(D4a)′. In certain embodiments, R^(D4)′ is —OC(═O)OMe. In certain embodiments, R^(D4)′ is —OC(═O)O(t-Bu).

In certain embodiments, R^(D4a)′ is substituted alkyl. In certain embodiments, R^(D4a)′ is unsubstituted alkyl. In certain embodiments, R^(D4a)′ is C₁₋₆ alkyl. In certain embodiments, R^(D4a)′ is methyl. In certain embodiments, R^(D4a)′ is ethyl. In certain embodiments, R^(D4a)′ is propyl. In certain embodiments, R^(D4a)′ is butyl. In certain embodiments, R^(D4a)′ is substituted alkenyl. In certain embodiments, R^(D4a)′ is unsubstituted alkenyl. In certain embodiments, R^(D4a)′ is vinyl. In certain embodiments, R^(D4a)′ is substituted alkynyl. In certain embodiments, R^(D4a)′ is unsubstituted alkynyl. In certain embodiments, R^(D4a)′ is ethynyl. In certain embodiments, R^(D4a)′ is substituted carbocyclyl. In certain embodiments, R^(D4a)′ is unsubstituted carbocyclyl. In certain embodiments, R^(D4a)′ is substituted heterocyclyl. In certain embodiments, R^(D4a)′ is unsubstituted heterocyclyl. In certain embodiments, R^(D4a)′ is substituted aryl. In certain embodiments, R^(D4a)′ is unsubstituted aryl. In certain embodiments, R^(D4a)′ is substituted phenyl. In certain embodiments, R^(D4a)′ is unsubstituted phenyl. In certain embodiments, R^(D4a)′ is substituted heteroaryl. In certain embodiments, R^(D4a)′ is unsubstituted heteroaryl. In certain embodiments, R^(D4a)′ is substituted pyridyl. In certain embodiments, R^(D4a)′ is unsubstituted pyridyl.

In compounds of Formula (II), R^(D)′ may include a substituent R^(D5)′. In certain embodiments, R^(D5)′ is H. In certain embodiments, R^(D5)′ is substituted alkyl. In certain embodiments, R^(D5)′ is unsubstituted alkyl. In certain embodiments, R^(D5)′ is C₁₋₆ alkyl. In certain embodiments, R^(D5)′ is methyl. In certain embodiments, R^(D5)′ is ethyl. In certain embodiments, R^(D5)′ is propyl. In certain embodiments, R^(D5)′ is butyl. In certain embodiments, R^(D5)′ is a nitrogen protecting group. In certain embodiments, R^(D5)′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.

In certain embodiments, R^(D1)′ and R^(D2)′ are each hydrogen. In certain embodiments, R^(D1)′ and R^(D3)′ are each hydrogen. In certain embodiments, R^(D2)′ and R^(D3)′ are each hydrogen. In certain embodiments, R^(D1)′, R^(D2)′, and R^(D3)′ are each hydrogen. In certain embodiments, R^(D1)′, R^(D2)′, and R^(D3)′, and R^(D5)′ are each hydrogen.

In certain embodiments, a′ is 1. In certain embodiments, a′ is 2.

In certain embodiments, z′ is 0. In certain embodiments, z′ is 1. In certain embodiments, z′ is 2. In certain embodiments, z′ is 3. In certain embodiments, z′ is 4. In certain embodiments, z′ is 5. In certain embodiments, z′ is 6.

In certain embodiments, Y^(Z)′ is —O—. In certain embodiments, Y^(Z)′ is ═O. In certain embodiments, Y^(Z)′ is —S—. In certain embodiments, Y^(Z)′ is ═S. In certain embodiments, Y^(Z)′ is —NR^(D6)′—, wherein R^(D6)′ is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group. In certain embodiments, Y^(Z)′ is —NH—. In certain embodiments, Y^(Z)′ is —NCH₃—. In certain embodiments, Y^(Z)′ is —N(BOC)—. In certain embodiments, Y^(Z)′ is —N(Fmoc)-. In certain embodiments, Y^(Z)′ is —N(Cbz)—. In certain embodiments, Y^(Z)′ is —N(Bn)-. In certain embodiments, Y^(Z)′ is ═NR^(D6)′, wherein R^(D6)′ is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group. In certain embodiments, Y^(Z)′ is ═NH. In certain embodiments, Y^(Z)′ is ═NCH₃. In certain embodiments, Y^(Z)′ is ═NTs. In certain embodiments, Y^(Z)′ is ═NBn. In certain embodiments, Y^(Z)′ is ═NCH(Ph)₂.

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

In certain embodiments, R^(D)′ is of the formula:

Compounds of Formula (II) or (V) include an aryl Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, k′ is 0. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, k′ is 1. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, k′ is 2. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, k′ is 3. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, k′ is 4. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

Compounds of Formula (II) or (V) include an aryl Ring A′ optionally substituted with one or more R^(A)′ groups. In certain embodiments, X′, Y′, and Z′ are bonds, and Cy is hydrogen. In certain embodiments, k′ is 0. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, k′ is 1. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, k′ is 2. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In compounds of Formula (II) or (V), Ring A′ may be substituted with one or more R^(A)′ groups. In certain embodiments, at least one R^(A)′ is H. In certain embodiments, at least two R^(A)′ groups are H. In certain embodiments, at least three R^(A)′ groups are H. In certain embodiments, at least four R^(A)′ groups are H. In certain embodiments, at least one R^(A)′ is halogen. In certain embodiments, at least one R^(A)′ is F. In certain embodiments, at least one R^(A)′ is Cl. In certain embodiments, at least one R^(A)′ is Br. In certain embodiments, at least one R^(A)′ is I (iodine). In certain embodiments, at least one R^(A)′ is substituted acyl. In certain embodiments, at least one R^(A)′ is —C(═O)N(R^(A1)′)₂. In certain embodiments, at least one R^(A)′ is —C(═O)NHR^(A1)′. In certain embodiments, at least one R^(A)′ is —C(═O)NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(A)′ is —C(═O)NHMe. In certain embodiments, at least one R^(A)′ is —C(═O)NH₂. In certain embodiments, at least one R^(A)′ is unsubstituted acyl. In certain embodiments, at least one R^(A)′ is acetyl. In certain embodiments, at least one R^(A)′ is substituted alkyl. In certain embodiments, at least one R^(A)′ is substituted methyl. In certain embodiments, at least one R^(A)′ is unsubstituted alkyl. In certain embodiments, at least one R^(A)′ is C₁₋₆ alkyl. In certain embodiments, at least one R^(A)′ is methyl. In certain embodiments, at least one R^(A)′ is ethyl. In certain embodiments, at least one R^(A)′ is propyl. In certain embodiments, at least one R^(A)′ is butyl. In certain embodiments, at least one R^(A)′ is substituted alkenyl. In certain embodiments, at least one R^(A)′ is unsubstituted alkenyl. In certain embodiments, at least one R^(A)′ is substituted alkynyl. In certain embodiments, at least one R^(A)′ is unsubstituted alkynyl. In certain embodiments, at least one R^(A)′ is substituted carbocyclyl. In certain embodiments, at least one R^(A)′ is unsubstituted carbocyclyl. In certain embodiments, at least one R^(A)′ is substituted heterocyclyl. In certain embodiments, at least one

R^(A)′ is unsubstituted heterocyclyl. In certain embodiments, at least one R^(A)′ is

In certain embodiments, at least one R^(A)′ is substituted aryl. In certain embodiments, at least one R^(A)′ is unsubstituted aryl. In certain embodiments, at least one R^(A)′ is substituted phenyl. In certain embodiments, at least one R^(A)′ is unsubstituted phenyl. In certain embodiments, at least one R^(A)′ is substituted heteroaryl. In certain embodiments, at least one R^(A)′ is unsubstituted heteroaryl. In certain embodiments, at least one R^(A)′ is substituted pyridyl. In certain embodiments, at least one R^(A)′ is unsubstituted pyridyl. In certain embodiments, at least one R^(A)′ is _OR″. In certain embodiments, at least one R^(A)′ is —O(C₁₋₆ alkyl). In certain embodiments, at least one R^(A)′ is —OMe. In certain embodiments, at least one R^(A)′ is —OH. In certain embodiments, at least one R^(A)′ is —N(R^(A1)′)₂. In certain embodiments, at least one R^(A)′ is —NH₂. In certain embodiments, at least one R^(A)′ is —SR^(A1)′. In certain embodiments, at least one R^(A)′ is —SH. In certain embodiments, at least one R^(A)′ is —NR^(A1)′C(═O)N(R^(A1)′)₂. In certain embodiments, at least one R^(A)′ is —NHC(═O)N(R^(A1)′)₂. In certain embodiments, at least one R^(A)′ is —NHC(═O)NHR^(A1)′. In certain embodiments, at least one R^(A)′ is —NHC(═O)NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(A)′ is —NHC(═O)NHMe. In certain embodiments, at least one R^(A)′ is —NHC(═O)NH₂. In certain embodiments, at least one R^(A)′ is —NR^(A1)′C(═O)NHR^(A1)′. In certain embodiments, at least one R^(A)′ is —NR^(A1)′C(═O)NH₂. In certain embodiments, at least one R^(A)′ is —NR^(A1)′S(═O)₂R^(A1)′. In certain embodiments, at least one R^(A)′ is —NHS(═O)₂R^(A1)′. In certain embodiments, at least one R^(A)′ is —NHS(═O)₂(C₁₋₆ alkyl). In certain embodiments, at least one R^(A)′ is —NHS(═O)₂Me. In certain embodiments, at least one R^(A)′ is —S(═O)₂N(R^(A1)′)₂. In certain embodiments, at least one R^(A)′ is —S(═O)₂N(R^(A1)′)₂. In certain embodiments, at least one R^(A)′ is —S(═O)₂N(C₁₋₆ alkyl)₂. In certain embodiments, at least one R^(A)′ is —S(═O)₂NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(A)′ is —S(═O)₂NH(t-Bu). In certain embodiments, at least one R^(A)′ is —S(═O)₂NH₂.

In compounds of Formula (II) or (V), Ring C′ may be substituted with one or more R^(B)′ groups. In certain embodiments, at least one R^(B)′ is H. In certain embodiments, at least two R^(B)′ groups are H. In certain embodiments, at least three R^(B)′ groups are H. In certain embodiments, at least four R^(B)′ groups are H. In certain embodiments, at least one R^(B)′ is halogen. In certain embodiments, at least one R^(B)′ is F. In certain embodiments, at least one R^(B)′ is Cl. In certain embodiments, at least one R^(B)′ is Br. In certain embodiments, at least one R^(B)′ is I (iodine). In certain embodiments, at least one R^(B)′ is substituted acyl. In certain embodiments, at least one R^(B)′ is —C(═O)N(R^(A1)′)₂. In certain embodiments, at least one R^(B)′ is —C(═O)NHR^(A1)′. In certain embodiments, at least one R^(B)′ is —C(═O)NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(B)′ is —C(═O)NHMe. In certain embodiments, at least one R^(B)′ is —C(═O)NH₂. In certain embodiments, at least one R^(B)′ is unsubstituted acyl. In certain embodiments, at least one R^(B)′ is acetyl. In certain embodiments, at least one R^(B)′ is substituted alkyl. In certain embodiments, at least one R^(B)′ is substituted methyl. In certain embodiments, at least one R^(B)′ is unsubstituted alkyl. In certain embodiments, at least one R^(B)′ is C₁₋₆ alkyl. In certain embodiments, at least one R^(B)′ is methyl. In certain embodiments, at least one R^(B)′ is ethyl. In certain embodiments, at least one R^(B)′ is propyl. In certain embodiments, at least one R^(B)′ is butyl. In certain embodiments, at least one R^(B)′ is —CF₃. In certain embodiments, at least one R^(B)′ is substituted alkenyl. In certain embodiments, at least one R^(B)′ is unsubstituted alkenyl. In certain embodiments, at least one R^(B)′ is substituted alkynyl. In certain embodiments, at least one R^(B)′ is unsubstituted alkynyl. In certain embodiments, at least one R^(B)′ is substituted carbocyclyl. In certain embodiments, at least one R^(B)′ is unsubstituted carbocyclyl. In certain embodiments, at least one R^(B)′ is substituted heterocyclyl. In certain embodiments, at least one R^(B)′ is unsubstituted heterocyclyl. In certain embodiments, at least one R^(B)′ is substituted aryl. In certain embodiments, at least one R^(B)′ is unsubstituted aryl. In certain embodiments, at least one R^(B)′ is substituted phenyl. In certain embodiments, at least one R^(B)′ is unsubstituted phenyl. In certain embodiments, at least one R^(B)′ is substituted heteroaryl. In certain embodiments, at least one R^(B)′ is unsubstituted heteroaryl. In certain embodiments, at least one R^(B)′ is substituted pyridyl. In certain embodiments, at least one R^(B)′ is unsubstituted pyridyl. In certain embodiments, at least one R^(B)′ is —O^(A1). In certain embodiments, at least one R^(B)′ is —O(C₁₋₆ alkyl). In certain embodiments, at least one R^(B)′ is —OMe. In certain embodiments, at least one R^(B)′ is —OH. In certain embodiments, at least one R^(B)′ is —N(R^(A1)′)₂. In certain embodiments, at least one R^(B)′ is —NH₂. In certain embodiments, at least one R^(B)′ is —SR^(A1)′. In certain embodiments, at least one R^(B)′ is —SH. In certain embodiments, at least one R^(B)′ is —NR^(A1)′C(═O)N(R^(A1)′)₂. In certain embodiments, at least one R^(B)′ is NHC(═O)N(R^(A1)′)₂. In certain embodiments, at least one R^(B)′ is —NHC(═O)NHR^(A1)′. In certain embodiments, at least one R^(B)′ is —NHC(═O)NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(B)′ is —NHC(═O)NHMe. In certain embodiments, at least one R^(B)′ is —NHC(═O)NH₂. In certain embodiments, at least one R^(B)′ is NR^(A1)′C(═O)NHR^(A1)′. In certain embodiments, at least one R^(B)′ is —NR^(A1)′C(═O)NH₂. In certain embodiments, at least one R^(B)′ is —NR^(A1)′S(═O)₂R^(A1)′. In certain embodiments, at least one R^(B)′ is NHS(═O)₂R^(A1)′. In certain embodiments, at least one R^(B)′ is —NHS(═O)₂(C₁₋₆ alkyl). In certain embodiments, at least one R^(B)′ is —NHS(═O)₂Me. In certain embodiments, at least one R^(B)′ is —S(═O)₂N(R^(A1)′)₂. In certain embodiments, at least one R^(B)′ is —S(═O)₂N(R^(A1)′)₂. In certain embodiments, at least one R^(B)′ is —S(═O)₂N(C₁₋₆ alkyl)₂. In certain embodiments, at least one R^(B)′ is —S(═O)₂NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(B)′ is —S(═O)₂NH(t-Bu). In certain embodiments, at least one R^(B)′ is —S(═O)₂NH₂. In certain embodiments, at least one R^(B)′ is substituted imidazole. In certain embodiments, at least one R^(B)′ is substituted piperidine. In certain embodiments, at least one R^(B)′ substituted piperizine. In certain embodiments, at least one R^(B)′ substituted pyrrolidine. In certain embodiments, at least one R^(B)′ is substituted morpholine. In certain embodiments, at least one R^(B)′ is substituted diazapane. In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, at least one R^(B)′ is

In certain embodiments, two R^(B)′ groups are are joined to form a 1,3 dioxolane. In certain embodiments, two R^(B)′ groups are are joined to form a 1,3 dioxolane which is fused to aryl Ring C′, together comprising an optionally substituted benzodioxolane. In certain embodiments, two R^(B)′ groups are joined to form a 1,2,3-thiadiazole. In certain embodiments, two R^(B)′ groups are joined to form a 1,2,3-thiadiazole which is fused to aryl Ring C′, together comprising an optionally substituted. benzo[d][1,2,3]thiadiazole.

In certain embodiments, at least one R^(A1)′ is H. In certain embodiments, at least one R^(A1)′ is substituted acyl. In certain embodiments, at least one R^(A1)′ is unsubstituted acyl. In certain embodiments, at least one R^(A1)′ is acetyl. In certain embodiments, at least one R^(A1)′ is substituted alkyl. In certain embodiments, at least one R^(A1)′ is unsubstituted alkyl. In certain embodiments, at least one R^(A1)′ is C₁₋₆ alkyl. In certain embodiments, at least one R^(A1)′ is methyl. In certain embodiments, at least one R^(A1)′ is ethyl. In certain embodiments, at least one R^(A1)′ is propyl. In certain embodiments, at least one R^(A1)′ is butyl. In certain embodiments, at least one R^(A1)′ is substituted alkenyl. In certain embodiments, at least one R^(A1)′ is unsubstituted alkenyl. In certain embodiments, at least one R^(A1)′ is substituted alkynyl. In certain embodiments, at least one R^(A1)′ is unsubstituted alkynyl. In certain embodiments, at least one R^(A1)′ is substituted carbocyclyl. In certain embodiments, at least one R^(A1)′ is unsubstituted carbocyclyl. In certain embodiments, at least one R^(A1)′ is substituted heterocyclyl. In certain embodiments, at least one R^(A1)′ is unsubstituted heterocyclyl. In certain embodiments, at least one R^(A1)′ is substituted aryl. In certain embodiments, at least one R^(A1)′ is unsubstituted aryl. In certain embodiments, at least one R^(A1)′ is substituted phenyl. In certain embodiments, at least one R^(A1)′ is unsubstituted phenyl. In certain embodiments, at least one R^(A1)′ is substituted heteroaryl. In certain embodiments, at least one R^(A1)′ is unsubstituted heteroaryl. In certain embodiments, at least one R^(A1)′ is substituted pyridyl. In certain embodiments, at least one R^(A1)′ is unsubstituted pyridyl. In certain embodiments, at least one R^(A1)′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^(A1)′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^(A1)′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^(A1)′ is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^(A1)′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^(A1)′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.

In compounds of Formula (II) or (V), two R^(A1)′ groups may be joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring. In certain embodiments, two R^(A1)′ groups are joined to form a substituted carbocyclic ring. In certain embodiments, two R^(A1)′ groups are joined to form an unsubstituted carbocyclic ring. In certain embodiments, two R^(A1)′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^(A1)′ groups are joined to form an unsubstituted heterocyclic ring. In certain embodiments, two R^(A1)′ groups are joined to form a substituted aryl ring. In certain embodiments, two R^(A1)′ groups are joined to form an unsubstituted aryl ring. In certain embodiments, two R^(A1)′ groups are joined to form a substituted phenyl ring. In certain embodiments, two R^(A1)′ groups are joined to form an unsubstituted phenyl ring. In certain embodiments, two R^(A1)′ groups are joined to form a substituted heteroaryl ring. In certain embodiments, two R^(A1)′ groups are joined to form an unsubstituted heteroaryl ring.

In certain embodiments, R^(A)′ is —OR^(A1)′ and k′ is 1. In certain embodiments, R^(A)′ is —O(C₁₋₆ alkyl) and k′ is 1. In certain embodiments, R^(A)′ is —OMe and k′ is 1. In certain embodiments, R^(A)′ is —OH and k′ is 1.

In certain embodiments, R^(A)′ is substituted C₁₋₆ alkyl; and k′ is 1. In certain embodiments, R^(A)′ is unsubstituted C₁₋₆ alkyl; and k′ is 1. In certain embodiments, R^(A)′ is methyl; and k′ is 1. In certain embodiments, R^(A)′ is —CF₃; and k′ is 1. In certain embodiments, R^(A)′ is ethyl; and k′ is 1. In certain embodiments, R^(A)′ is propyl; and k′ is 1. In certain embodiments, R^(A)′ is butyl; and k′ is 1. In certain embodiments, R^(A)′ is propyl; and k′ is 1. In certain embodiments, R^(A)′ is butyl; and k′ is 1.

In certain embodiments, R^(A)′ is halogen; and k′ is 1. In certain embodiments, R^(A)′ is F; and k′ is 1. In certain embodiments, R^(A)′ is Cl; and k′ is 1. In certain embodiments, R^(A)′ is Br; and k′ is 1. In certain embodiments, R^(A)′ is I (iodine); and k′ is 1.

In certain embodiments, one instance of R^(A)′ is halogen, another instance of R^(A)′ is substituted C₁₋₆ alkyl; and k′ is 2. In certain embodiments, one instance of R^(A)′ is F, another instance of R^(A)′ is substituted C₁₋₆ alkyl; and k′ is 2. In certain embodiments, one instance of R^(A)′ is Cl, another instance of R^(A)′ is substituted C₁₋₆ alkyl; and k′ is 2. In certain embodiments, one instance of R^(A)′ is halogen, another instance of R^(A)′ is unsubstituted C₁₋₆ alkyl; and k′ is 2. In certain embodiments, one instance of R^(A)′ is F, another instance of R^(A)′ is unsubstituted C₁₋₆ alkyl; and k′ is 2. In certain embodiments, one instance of R^(A)′ is Cl, another instance of R^(A)′ is unsubstituted C₁₋₆ alkyl; and k′ is 2. In certain embodiments, one instance of R^(A)′ is halogen, another instance of R^(A)′ is methyl; and k′ is 2. In certain embodiments, one instance of R^(A)′ is F, another instance of R^(A)′ is methyl; and k′ is 2. In certain embodiments, one instance of R^(A)′ is Cl, another instance of R^(A)′ is methyl; and k′ is 2. In certain embodiments, one instance of R^(A)′ is halogen, another instance of R^(A)′ is —CF₃; and k′ is 2. In certain embodiments, one instance of R^(A)′ is F, another instance of R^(A)′ is —CF₃; and k′ is 2. In certain embodiments, one instance of R^(A)′ is Cl, another instance of R^(A)′ is —CF₃; and k′ is 2.

In compounds of Formula (II) or (V), linker X′, Y′, and Z′ are divalent linker moieties. In certain embodiments, X′ is a bond. In certain embodiments, X′ is a single bond. In certain embodiments, X′ is —CH₂. In certain embodiments, X′ is —CHR^(A)′. In certain embodiments, X′ is —CH. In certain embodiments, X′ is —C(R^(A)′)₂. In certain embodiments, X′ is —C. In certain embodiments, X′ is —N. In certain embodiments, X′ is —NR^(A)′. In certain embodiments, X′ is —O. In certain embodiments, X′ is —C═O. In certain embodiments, X′ is —O. In certain embodiments, X′ is —S. In certain embodiments, X′ may optionally form a 5 to 8 membered ring with R^(A)′ or R^(B)′. In certain embodiments, Y′ is a bond. In certain embodiments, Y′ is a single bond. In certain embodiments, Y′ is —CH₂. In certain embodiments, Y′ is —CHR^(A)′. In certain embodiments, Y′ is —CH. In certain embodiments, Y′ is —C(R^(A)′)₂. In certain embodiments, Y′ is —C. In certain embodiments, Y′ is —N. In certain embodiments, Y′ is —NR^(A)′. In certain embodiments, Y′ is —O. In certain embodiments, Y′ is —C═O. In certain embodiments, Y′ is —S. In certain embodiments, Y′ may optionally form a 5 to 8 membered ring with R^(A)′ or R^(B)′. In certain embodiments, Z′ is a bond. In certain embodiments, Z′ is a single bond. In certain embodiments, Z′ is —CH₂. In certain embodiments, Z′ is —CHR^(A)′. In certain embodiments, Z′ is —CH. In certain embodiments, Z′ is —C(R^(A)′)₂. In certain embodiments, Z′ is —C. In certain embodiments, Z′ is —N. In certain embodiments, Z′ is —NR^(A)′. In certain embodiments, Z′ is —O. In certain embodiments, Z′ is —C═O. In certain embodiments, Z′ is —S. In certain embodiments, Z′ may optionally form a 5 to 8 membered ring with R^(A)′ or R^(B)′.

In compounds of Formula (II) or (V), linker X′, Y′, and Z′ can be taken together to represent specific linking groups. In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together renresent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent a single bond.

In compounds of Formula (II) or (V), linker Q′ and U′ are divalent linker moieties. In certain embodiments, Q′ is —NR^(A)′. In certain embodiments, Q′ is —NH. In certain embodiments, Q′ is —C═O. In certain embodiments, Q′ is —NR^(A)′CO. In certain embodiments, Q′ is a bond. In certain embodiments, X′ may optionally form a 5 to 8 membered ring with R^(A)′ or R^(B)′. In certain embodiments, U′ is —NR^(A)′. In certain embodiments, U′ is —NH. In certain embodiments, U′ is —C═O. In certain embodiments, U′ is NR^(A)′CO. In certain embodiments, U′ is a bond. In certain embodiments, U′ may optionally form a 5 to 8 membered ring with R^(A)′ or R^(B)′.

In compounds of Formula (II) or (V), linker Q′ and U′ can be taken together to represent specific linking groups. In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

Cy of Formula (II) or (V) may be an optionally substituted aryl ring. In certain embodiments, Ring Cy is a substituted aryl ring. In certain embodiments, Cy is an unsubstituted aryl ring. In certain embodiments, Cy is a monocyclic aryl ring. In certain embodiments, Cy is substituted phenyl. In certain embodiments, Cy is unsubstituted phenyl. In certain embodiments, Cy is a bicyclic aryl ring. In certain embodiments, Cy is substituted naphthyl. In certain embodiments, Cy is unsubstituted naphthyl. In certain embodiments, Cy is an optionally substituted aryl ring fused with one or more optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl groups wherein the point of attachment is on the aryl ring.

Cy of Formula (II) or (V) may also be an optionally substituted heteroaryl ring. In certain embodiments, Cy is a substituted heteroaryl ring. In certain embodiments, Cy is an unsubstituted heteroaryl ring. In certain embodiments, Cy is a monocyclic heteroaryl ring. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with one heteroatom selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with two heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with three heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is substituted pyrrolyl. In certain embodiments, Cy is unsubstituted pyrrolyl. In certain embodiments, Cy is substituted furanyl. In certain embodiments, Cy is unsubstituted furanyl. In certain embodiments, Cy is substituted thienyl. In certain embodiments, Cy is unsubstituted thienyl. In certain embodiments, Cy is substituted pyrazolyl. In certain embodiments, Cy is unsubstituted pyrazolyl. In certain embodiments, Cy is substituted imidazolyl. In certain embodiments, Cy is unsubstituted imidazolyl. In certain embodiments, Cy is substituted oxazolyl. In certain embodiments, Cy is unsubstituted oxazolyl. In certain embodiments, Cy is substituted isoxazolyl. In certain embodiments, Cy is unsubstituted isoxazolyl. In certain embodiments, Cy is substituted thiazolyl. In certain embodiments, Cy is unsubstituted thiazolyl. In certain embodiments, Cy is substituted isothiazolyl. In certain embodiments, Cy is unsubstituted isothiazolyl. In certain embodiments, Cy is substituted triazolyl. In certain embodiments, Cy is unsubstituted triazolyl. In certain embodiments, Cy is substituted oxadiazolyl. In certain embodiments, Cy is unsubstituted oxadiazolyl. In certain embodiments, Cy is substituted thiadiazolyl. In certain embodiments, Cy is unsubstituted thiadiazolyl. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with one heteroatom selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with two heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with three heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is substituted pyridyl. In certain embodiments, Cy is unsubstituted pyridyl. In certain embodiments, Cy is substituted pyridazinyl. In certain embodiments, Cy is unsubstituted pyridazinyl. In certain embodiments, Cy is substituted pyrimidinyl. In certain embodiments, Cy is unsubstituted pyrimidinyl. In certain embodiments, Cy is substituted pyrazinyl. In certain embodiments, Cy is unsubstituted pyrazinyl. In certain embodiments, Cy is substituted triazinyl. In certain embodiments, Cy is unsubstituted triazinyl. In certain embodiments, Cy is an optionally substituted heteroaryl ring fused with one or more optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl groups wherein the point of attachment is on any one of the heteroaryl ring, or carbocyclic, heterocyclic, aryl, or heteroaryl groups, as valency permits. In certain embodiments, Cy is a bicyclic heteroaryl ring. In certain embodiments, Cy is an optionally substituted heteroaryl ring fused with an optionally substituted phenyl ring. In certain embodiments, Cy is substituted indolyl. In certain embodiments, Cy is unsubstituted indolyl. In certain embodiments, Cy is substituted isoindolyl. In certain embodiments, Cy is unsubstituted isoindolyl. In certain embodiments, Cy is substituted indazolyl. In certain embodiments, Cy is unsubstituted indazolyl. In certain embodiments, Cy is substituted benzothienyl. In certain embodiments, Cy is unsubstituted benzothienyl. In certain embodiments, Cy is substituted isobenzothienyl. In certain embodiments, Cy is unsubstituted isobenzothienyl. In certain embodiments, Cy is substituted benzofuranyl. In certain embodiments, Cy is unsubstituted benzofuranyl. In certain embodiments, Cy is substituted benzoisofuranyl. In certain embodiments, Cy is unsubstituted benzoisofuranyl. In certain embodiments, Cy is substituted benzimidazolyl. In certain embodiments, Cy is unsubstituted benzimidazolyl. In certain embodiments, Cy is substituted benzoxazolyl. In certain embodiments, Cy is unsubstituted benzoxazolyl. In certain embodiments, Cy is substituted benzisoxazolyl. In certain embodiments, Cy is unsubstituted benzisoxazolyl. In certain embodiments, Cy is substituted benzothiazolyl. In certain embodiments, Cy is unsubstituted benzothiazolyl. In certain embodiments, Cy is substituted benzisothiazolyl. In certain embodiments, Cy is unsubstituted benzisothiazolyl. In certain embodiments, Cy is substituted benzotriazolyl. In certain embodiments, Cy is unsubstituted benzotriazolyl. In certain embodiments, Cy is substituted benzoxadiazolyl. In certain embodiments, Cy is unsubstituted benzoxadiazolyl. In certain embodiments, Cy is substituted quinolinyl. In certain embodiments, Cy is unsubstituted quinolinyl. In certain embodiments, Cy is substituted isoquinolinyl. In certain embodiments, Cy is unsubstituted isoquinolinyl. In certain embodiments, Cy is substituted cinnolinyl. In certain embodiments, Cy is unsubstituted cinnolinyl. In certain embodiments, Cy is substituted quinoxalinyl. In certain embodiments, Cy is unsubstituted quinoxalinyl. In certain embodiments, Cy is substituted phthalazinyl. In certain embodiments, Cy is unsubstituted phthalazinyl. In certain embodiments, Cy is substituted quinazolinyl. In certain embodiments, Cy is unsubstituted quinazolinyl. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position.

In compounds of Formula (II) or (V), Cy may be substituted with one or more R^(X)′ groups. In certain embodiments, at least one R^(X)′ is H. In certain embodiments, at least two R^(X)′ groups are H. In certain embodiments, at least three R^(X)′ groups are H. In certain embodiments, at least four R^(X)′ groups are H. In certain embodiments, at least one R^(X)′ is halogen. In certain embodiments, at least one R^(X)′ is F. In certain embodiments, at least one R^(X)′ is Cl. In certain embodiments, at least one R^(X)′ is Br. In certain embodiments, at least one R^(X)′ is I (iodine). In certain embodiments, at least one R^(X)′ is substituted acyl. In certain embodiments, at least one R^(X)′ is —C(═O)N(R^(A1)′)₂. In certain embodiments, at least one R^(X)′ is —C(═O)NHR^(A1)′. In certain embodiments, at least one R^(X)′ is —C(═O)NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(X)′ is —C(═O)NHMe. In certain embodiments, at least one R^(X)′ is —C(═O)NH₂. In certain embodiments, at least one R^(X)′ is unsubstituted acyl. In certain embodiments, at least one R^(X)′ is acetyl. In certain embodiments, at least one R^(X)′ is substituted alkyl. In certain embodiments, at least one R^(X)′ is substituted methyl. In certain embodiments, at least one R^(X)′ is unsubstituted alkyl. In certain embodiments, at least one R^(X)′ is C₁₋₆ alkyl. In certain embodiments, at least one R^(X)′ is methyl. In certain embodiments, at least one R^(X)′ is ethyl. In certain embodiments, at least one R^(X)′ is propyl. In certain embodiments, at least one R^(X)′ is butyl. In certain embodiments, at least one R^(X)′ is substituted alkenyl. In certain embodiments, at least one R^(X)′ is unsubstituted alkenyl. In certain embodiments, at least one R^(X)′ is substituted alkynyl. In certain embodiments, at least one R^(X)′ is unsubstituted alkynyl. In certain embodiments, at least one R^(X)′ is substituted carbocyclyl. In certain embodiments, at least one R^(X)′ is unsubstituted carbocyclyl. In certain embodiments, at least one R^(X)′ is substituted heterocyclyl. In certain embodiments, at least one R^(X)′ is unsubstituted heterocyclyl. In certain embodiments, at least one R^(X)′ is substituted aryl. In certain embodiments, at least one R^(X)′ is unsubstituted aryl. In certain embodiments, at least one R^(X)′ is substituted phenyl. In certain embodiments, at least one R^(X)′ is unsubstituted phenyl. In certain embodiments, at least one R^(X)′ is substituted heteroaryl. In certain embodiments, at least one R^(X)′ is unsubstituted heteroaryl. In certain embodiments, at least one R^(X)′ is substituted pyridyl. In certain embodiments, at least one R^(X)′ is unsubstituted pyridyl. In certain embodiments, at least one R^(X)′ is —OR^(A1)′. In certain embodiments, at least one R^(X)′ is —O(C₁₋₆ alkyl). In certain embodiments, at least one R^(X)′ is —OMe. In certain embodiments, at least one R^(X)′ is —OH. In certain embodiments, at least one R^(X)′ is —N(R^(A1)′)₂. In certain embodiments, at least one R^(X)′ is —NH₂. In certain embodiments, at least one R^(X)′ is SR^(A1)′. In certain embodiments, at least one R^(X)′ is —SH. In certain embodiments, at least one R^(X)′ is —NR^(A1)′C(═O)N(R^(A1)′)₂. In certain embodiments, at least one R^(X)′ is —NHC(═O)N(R^(A1)′)₂. In certain embodiments, at least one R^(X)′ is —NHC(═O)NHR^(A1)′. In certain embodiments, at least one R^(X)′ is —NHC(═O)NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(X)′ is —NHC(═O)NHMe. In certain embodiments, at least one R^(X)′ is —NHC(═O)NH₂. In certain embodiments, at least one R^(X)′ is —NR^(A1)′C(═O)NHR^(A1)′. In certain embodiments, at least one R^(X)′ is —NR^(A1)′C(═O)NH₂. In certain embodiments, at least one R^(X)′ is —NR^(A1)′S(═O)₂R^(A1)′. In certain embodiments, at least one R^(X)′ is —NHS(═O)₂R^(A1)′. In certain embodiments, at least one R^(X)′ is —NHS(═O)₂(C₁₋₆ alkyl). In certain embodiments, at least one R^(X)′ is —NHS(═O)₂Me. In certain embodiments, at least one R^(X)′ is —S(═O)₂N(R^(A1)′)₂. In certain embodiments, at least one R^(X)′ is —S(═O)₂N(R^(A1)′)₂. In certain embodiments, at least one R^(X)′ is —S(═O)₂N(C₁₋₆ alkyl)₂. In certain embodiments, at least one R^(X)′ is —S(═O)₂NH(C₁₋₆ alkyl). In certain embodiments, at least one R^(X)′ is —S(═O)₂NH(t-Bu). In certain embodiments, at least one R^(X)′ is —S(═O)₂NH₂. In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiments, at least one R^(X)′ is

In certain embodiment, a compound of the invention is a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (A), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (I-11), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (I-11), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (V), or a pharmaceutically acceptable salt thereof.

In certain embodiments, compounds of the present invention include those which:

-   -   exhibit kinase inhibitory activity,     -   exhibit the ability to inhibit transforming growth factor         b-activated kinase-1 (TAK1), hemopoietic cell kinase (HCK) or         both TAK1 and HCK,     -   exhibit the ability to inhibit hematopoietic progenitor kinase 1         (HPK1, also known as mitogen-activated protein kinase kinase         kinase kinase 1 or MAP4K1),     -   exhibit the ability to inhibit Bruton's tyrosine kinase (BTK),         v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC)         family of kinases or both BTK and SRC,     -   exhibit cytotoxic or growth inhibitory effect on WM cell lines         maintained in vitro or in animal studies using a scientifically         acceptable cancer cell xenograft model; and/or     -   exhibit a therapeutic profile (e.g., optimum safety and curative         effect) that is superior to     -   existing chemotherapeutic agents.

As used herein “kinase” refers to a large class of enzymes which catalyze the transfer of the γ-phosphate from ATP to the hydroxyl group on the side chain of Ser/Thr or Tyr in proteins and peptides and are intimately involved in the control of various important cell functions, perhaps most notably: signal transduction, differentiation and proliferation. There are estimated to be about 2,000 distinct protein kinases in the human body and although each of these phosphorylates particular protein/peptide substrates, they all bind the same second substrate ATP in a highly conserved pocket. About 50% of the known oncogene products are protein tyrosine kinases PTKs and their kinase activity has been shown to lead to cell transformation.

In certain embodiments, the kinase to be inhibited is involved in the myeloid differentiation primary response gene (88) (MYD88) signaling pathway. For example, the kinase is Transforming growth factor b-activated kinase-1 (TAK1) or Hemopoietic cell kinase (HCK). In certain embodiments, the compound of the invention inhibits TAK1, HCK, or both TAK1 and HCK.

Myeloid differentiation primary response gene (88) (MYD88) L265P is a widely expressed somatic mutation in WM patients that supports NF-NFκB signaling through stimulation of BTK, IRAK1/4, TAK1. MYD88 is an adaptor molecule for Toll-like receptors (TLR) with the exception of TLR-3 and interleukin-1 receptor (IL-1R) signaling. Following TLR or IL-1R stimulation, MYD88 is recruited to the activated receptor complex as a homodimer which then complexes with interleukin-1 receptor-associated kinase 4 (IRAK4) and activates IRAK1 and IRAK2. Tumor necrosis factor receptor associated factor 6 (TRAF6) is then activated by IRAK1 leading to NFκB activation via IκBα phosphorylation and TAK1 activation.

Transforming growth factor b-activated kinase-1 (TAK1; also known as MAP3K7) is a member of the serine/threonine protein kinase family. This kinase mediates the signaling transduction induced by TGF beta and morphogenetic protein (BMP), and controls a variety of cell functions including transcription regulation and apoptosis. TAK1 knockout is embryonic lethal to mice. Conditional knock-down of TAK1 in adult mice results in systemic inflammation, spenomegaly, degeneration in heart, kidneys and liver and increased proliferation and differentiation of myeloid progenitor cells. TAK1 is located downstream of Myd88, Bruton's tyrosine kinase (BTK), and interleukin-1 receptor-associated kinase (IRAK), and is being investigated for its role in innate immunity, inflammatory response, and Ras-dependent cancers.

Hemopoietic cell kinase (HCK) is a non-receptor tyrosine-protein kinase found in hematopoietic cells and is known to interact with Bruton's tyrosine kinase (BTK) upon activation by B cell receptors (Proc. Natl. Acad. Sci. USA. 1994, 91(17), 8152-55). HCK transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. It acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, it mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. It also plays a role in the release of inflammatory molecules, promotes reorganization of the actin cytoskeleton and actin polymerization, and formation of podosomes and cell protrusions.

Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 serine/threonine kinase super family. HPK1 is also known as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1). HPK1 is a tissue-specific upstream activator of the MEKK/JNK/SAPK signaling pathway. HPK1 diminishes T cell receptor (TCR) signaling activity and T cell proliferation by phosphorylating the adaptor protein SLP-76. Cytosolic HPK1 is recruited to the TCR complex, and its kinase activity is induced upon the engagement of the TCR. Overexpression of HPK1 suppresses TCR-induced activation of AP-1-dependent gene transcription in a kinase-dependent manner, suggesting that the kinase activity of HPK1 is required to inhibit the Erk MAPK pathway. This blockage of the Erk MAPK pathway is thought to be the inhibitory mechanism that negatively regulates TCR-induced IL-2 gene transcription (Immunol. Res. 2012, 54(1-3), 262-65). In certain embodiments, the compounds of the invention, such as the compounds of Formula (A), (I-11), (II), or (V) (e.g., compounds of Formula (A-1)-(A-18)), inhibit HPK1.

In certain embodiments, the compounds of the invention are selective inhibitors of TAK1, HCK, or HPK1. The term “selective inhibitor” as used herein is understood to mean that in contrast to many kinase inhibitors of the prior art, the compounds do not act on a variety of kinases but act specifically on TAK1, HCK, or HPK1. In certain embodiments, the compounds of the invention inhibit one or more kinases in additon to TAK1, HCK, or HPK1 such as BTK or the SRC family of kinases. In certain embodiments of the invention, the specificity of the inhibitors is given by the IC₅₀ value. In some embodiments, the IC₅₀ value for a selective inhibitor is <100 μM for TAK1, HCK, or HPK1, but >100 μM for other kinases.

The IC₅₀ value is defined as the concentration of inhibitor required to inhibit 50% of the kinase activity. In certain embodiments, the compounds of the invention may exhibit IC₅₀ values <100 μM. In certain other embodiments, the compounds exhibit IC₅₀ values <50 μM. In certain other embodiments, the compounds exhibit IC₅₀ values<40 μM. In certain other embodiments, the compounds exhibit IC₅₀ values<30 μM. In certain other embodiments, the compounds exhibit IC₅₀ values <20 μM. In certain other embodiments, the compounds exhibit IC₅₀ values<10 μM. In certain other embodiments, the compounds exhibit IC₅₀ values<7.5 μM. In certain embodiments, the compounds exhibit IC₅₀ values<5 μM. In certain other embodiments, the compounds exhibit IC₅₀ values<2.5 μM. In certain embodiments, the compounds exhibit IC₅₀ values<1 μM. In certain embodiments, the compounds exhibit IC₅₀ values<0.75 μM. In certain embodiments, the compounds exhibit IC₅₀ values<0.5 μM. In certain embodiments, the compounds exhibit IC₅₀ values<0.25 μM. In certain embodiments, the compounds exhibit IC₅₀ values<0.1 μM. In certain other embodiments, the compounds exhibit IC₅₀ values<75 nM. In certain other embodiments, the compounds exhibit IC₅₀ values<50 nM. In certain other embodiments, the compounds exhibit IC₅₀ values<25 nM. In certain other embodiments, the compounds exhibit IC₅₀ values<10 nM. In other embodiments, the compounds exhibit IC₅₀ values<7.5 nM. In other embodiments, the compounds exhibit IC₅₀ values<5 nM.

In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit HCK selectively. In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit TAK1 selectively. A non-limiting example of a selective TAK1 inhibitor is:

In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit both TAK1 and HCK. A non-limiting example of a dual TAK1/HCK inhibitor is:

In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit HPK1 selectively. A non-limiting example of a selective HPK1 inhibitor is:

Also, provided are methods to treat B cell neoplasms using compounds of the invention in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase. In certain embodiments, one or more compounds of the invention are used in combination with an inhibitor of the phosphoinositide 3-kinase delta isoform (PI3Kδ). In certain embodiments, combinations of 2, 3, 4, 5, 6,7, 8, 9, 10, or more of the agents described herein are used for treating WM. In certain embodiments, the agents described herein are used in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.

Bruton's tyrosine kinase (BTK) is a key signaling enzyme expressed in all hematopoietic cells types except T lymphocytes and natural killer cells. BTK plays an essential role in the B cell signaling pathway linking cell surface B cell receptor BCR stimulation to downstream intracellular responses. BTK is a key regulator of B cell development activation signaling and survival (Kurosaki, Curr. Op. Imm., 2000, 276-281; Schaeffer and Schwartzberg, Curr. Op. Imm., 2000, 282-288). In addition BTK plays a role in a number of other hematopoietic cell signaling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (FcepsilonRI) signaling in mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen stimulated platelet aggregation. See e.g., C. A. Jeffries, et al., J. Biol. Chem., 2003, 278, 26258-26264; N. J. Horwood, et al., J. Exp. Med., 2003, 197, 1603-1611; Iwaki et al., J. Biol. Chem., 2005, 280(48), 40261-40270; Vassilev et al., J. Biol. Chem., 1999, 274(3),1646-1656; and Quek et al., Curr. Biol., 1998, 8(20),1137-1140. Activated Btk interacts with MyD88 and TRIF, promoting the activation of MyD88-dependent and TRIF-dependent pathways (Nature Immunology, 2011, 12, 416-424).

BTK inhibitors are well-known in the art, and include, for example, ibrutinib and benzonaphthyridinones (see U.S. provisional patent application U.S. Ser. No. 61/716,273, filed Oct. 19, 2012). Additional non-limiting examples of BTK inhibitors are disclosed in WO 1999/054286, WO 2013/010380, WO 2009/137596, WO 2011/029043, WO 2010/056875, WO 2000/056737, and WO 2013/067277.

IRAK1 and 4 are serine/threonine-protein kinases that play a critical role in initiating innate immune response against foreign pathogens. They are involved in Toll-like receptor (TLR) and IL-1R signaling pathways, and are rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation of IRAK1 (Immunity, 1997, 7(6), 837-47). IRAK4-/-mice have abolished cellular responses to various IL-1 and TLR ligands and are severely impaired in their response to viral and bacterial challenges. IRAK1-/-mice show a similar but partial response.

IRAK1 and IRAK4 inhibitors are well-known in the art, and include, for example, those disclosed in WO 2003/030902, WO 2012/007375, G. M. Buckely et al., Biorg. Med. Chem. Lett., 2008, 18, 3211-3214, and G. M. Buckely et al., Biorg. Med. Chem. Lett., 2008, 18, 3656-3660, WO2013/074986, and U.S. provisional patent application, U.S. Ser. No. 61/727,640, filed Nov. 16, 2012.

In certain embodiments, the IRAK4 inhibitor is of formula:

or an analog thereof.

“Bone Marrow on X chromosome” kinase (BMX, also termed ETK) is a non-receptor tyrosine kinase and is activated downstream of phosphatidylinositol-3 kinase (PI-3K) and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC), but its substrates are unknown. Positional scanning peptide library screening revealed a marked preference for a priming phosphotyrosine (pY) in the −1 position. Potential substrates include multiple tyrosine kinases with kinase domain pYpY sites required for full activity. BMX has been found to phosphorylate residue Y577 of focal adhesion kinase (FAK) subsequent to Y576 phosphorylation by SRC. In addition, BMX loss by RNA interference and mouse embryonic fibroblasts (MEFs) from Bmx negative (Bmx⁻) mice displayed impaired FAK signaling. Insulin receptor (IR) phosphorylation similarly was decreased by BMX loss, as was hepatic IR phosphorylation in Bmx⁻mice. However, glucose tolerance was increased, reflecting a marked compensatory decrease in the activity of the AKT phosphatase PHLPP. These findings reveal a mechanism through which BMX functions as a central regulator of multiple kinase pathways.

BMX inhibitors are well-known in the art, and include, for example, those disclosed in U.S. Ser. Nos. 61/716,273 and 61/717,345, the contents of both of which are incorporated herein by reference. In certain embodiments, the BMX inhibitor is of formula:

or an analog thereof.

Phosphatidylinositol 3-kinases (PI3-kinases or PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. PI3Ks are a family of related intracellular signal transducer enzymes capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol (Ptdlns). Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by PI3KCA gene represents the catalytic subunit, which uses ATP to phosphorylate phosphatidylinositols (Ptdlns), Ptdlns4P and Ptdlns(4,5)P2. Of particular interest is the PI3K delta isoform, which is expressed in white blood cells and is mainly involved in the signaling, development, and survival of B cells.

PI3K inhibitors are well-known in the art, and include, for example, those disclosed in International PCT Publications WO 2013/088404, WO 2012/068096, and WO 2013/052699, which are incorporated herein by reference.

In certain embodiments, the PI3K inhibitor is

or its analogs.

Compounds of the invention may be combined with other kinase inhibitors to treat WM or other B cell neoplasms. In certain embodiments, a compound of the invention is administered with an inhibitor of Bruton's tyrosine kinase (BTK) to treat WM or other B cell neoplasm. In certain embodiments, a compound of the invention is administered with an inhibitor of interleukin-1 receptor-associated kinase 1 (IRAK1) to treat WM or other B cell neoplasm. In certain embodiments, a compound of the invention is administered with an inhibitor of phosphoinositide 3-kinase (PI3K) to treat WM or other B cell neoplasm. In certain embodiments, a compound of of the invention is administered with an inhibitor of the phosphoinositide 3-kinase delta isoform (PI3Kδ) to treat WM or other B cell neoplasm. In certain embodiments, a compound of of the invention is administered with two of any inhibitors of BTK, IRAK1, or PI3K to treat WM or other B cell neoplasm. In certain embodiments, a compound of the invention is administered with more than two of any inhibitors of BTK, IRAK1, or PI3K to treat WM or other B cell neoplasm.

The BTK inhibitors, the IRAK1 inhibitors, the IRAK4 inhibitors, and/or the PI3K inhibitors can be administered to the subject simultaneously or sequentially.

A “subject” or “patient” to which administration is contemplated includes, any animal. In some embodiments, a subject includes but is not limited to, humans, commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys) and experimental animals (e.g., mice, rats, non-human primates). A subject in need of treatment is a subject identified as having a B cell neoplasm, i.e., the subject has been diagnosed by a physician (e.g., using methods well known in the art) as having a B cell neoplasm. In certain embodiments, the subject in need of treatment is a subject suspected of having or developing a B cell neoplasm, such as a subject presenting one or more symptoms indicative of a B cell neoplasm. The term “subject in need of treatment” further includes people who once had a B cell neoplasm but whose signs and/or symptoms have been ameliorated (i.e., their cancer is in remission). The one or more symptoms or clinical features of B cell neoplasms include, but are not limited to, asymptomatic localized or generalized peripheral lymphadenopathy, plasmacytic difference, bone marrow involvement, autoimmune thrombocytopenia, peripheral blood villous lymphocytes, end organ damage (hypercalcemia, renal insufficiency, bone lesions), recurrent infections, elevated creatine, hyperuricemia, and hypoalbunemia.

In certain embodiments, the subject is diagnosed as having Waldenström's macroglobulinemia (WM). The subject may present one or more signs, symptoms, or clinical features of WM including anemia, hyper-viscosity, neuropathy, coagulopathies, splenomegaly, hepatomegaly, adenopathy, and an IgM serum paraprotein. In certain embodiments, the subject is diagnosed as having WM on the basis that the subject has a mutation at position 38182641 of chromosome 3p22.2. In some embodiments, the mutation results in a single nucleotide change from T to C in the MYD88 gene. In some embodiments, the mutation results in an amino acid change from leucine to proline at position 265 in the MYD88 gene. The mutation may be detected in a biological sample obtained from the subject using any suitable method known in the art, including but not limited to, direct sequencing of nucleic acid molecules, HPLC analysis, DNA chip technologies, and mass spectroscopy. Non-limiting examples of the biological sample include bone marrow, lymph node, spleen, or blood.

The terms “administer,” “administering,” or “administration,” as used herein refers to implanting, absorbing, ingesting, injecting, or inhaling an inventive compound, or a pharmaceutical composition thereof.

As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a B cell neoplasm. In certain embodiments, treatment may be administered after one or more signs or symptoms have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the B cell neoplasm. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

An “effective amount” of compounds of the invention refers to an amount sufficient to elicit the desired biological response, i.e., treating the B cell neoplasm. As will be appreciated by those of ordinary skill in this art, the effective amount of compounds of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount includes, but is not limited to, that amount necessary to slow, reduce, inhibit, ameliorate or reverse one or more signs and/or symptoms associated with a B cell neoplasm. In the treatment of Waldenström's macroglobulinemia, this may refer to a reduction in the levels of IgM serum paraprotein, reduction in anemia, reduction in hyper-viscosity, reduction in neuropathy, reduction in coagulopathies, reduction in splenomegaly, reduction in hepatomegaly, and reduction in adenopathy.

An effective amount of a compound may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations, for one or several days (depending on the mode of administration). In certain embodiments, the effective amount varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, from about 1.0 mg/kg to about 100 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.

One or more additional pharmaceutical agents, such as anti-cancer agents (e.g., chemotherapeutics), anti-inflammatory agents, steroids, immunosuppressants, radiation therapy, or other agents, can be used in combination with the compounds of of the invention in the treatment of a B cell neoplasm. The one or more additional pharmaceutical agents can be administered to the subject simultaneously or sequentially.

Exemplary chemotherapeutic agents include alkylating agents such as nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates, nitrosuoureas, and triazenes; antimetabolites such as folic acid analogs, pyrimidine analogs, in particular fluorouracil and cytosine arabinoside, and purine analogs; natural products such as vinca alkaloids epi-podophyllotoxins, antibiotics, enzymes, and biological response modifiers; and miscellaneous products such as platinum coordination complexes, anthracenedione, substituted urea such as hydroxyurea, methyl hydrazine derivatives, and adrenocorticoid suppressant.

Exemplary chemotherapeutic agents also include anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, paclitaxel, colchicine, cytochalasin B, emetine, maytansine, amsacrine, cisplatin, carboplatin, mitomycin, altretamine, cyclophosphamide, lomustine, and carmustine.

In yet another aspect, the present invention provides pharmaceutical compositions comprising an effective amount of a compound of of the invention, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs, and optionally a pharmaceutically acceptable excipient, for use in the treatment of a B cell neoplasm. In certain embodiments, provided by the invention are the compounds of of the invention, and pharmaceutically acceptable salts and compositions thereof, for use in the treatment of a B cell neoplasm. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is an amount useful for the treatment and/or prevention of a B cell neoplasm. In certain embodiments, the B cell neoplasm is, but is not limited to, Hodgkin's lymphomas and most non-Hodgkins lymphomas, such as, diffuse large B cell lymphoma, Follicular lymphoma, Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with Chronic lymphocytic leukemia), Mantle cell lymphoma (MCL), Burkitt lymphoma, Mediastinal large B cell lymphoma, Waldenström's macroglobulinemia, Nodal marginal zone B cell lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL), Intravascular large B-cell lymphoma, Primary effusion lymphoma and Lymphomatoid granulomatosis. An effective amount of a compound may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations, for one or several days (depending on the mode of administration). In certain embodiments, the effective amount varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.

Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing a compound of of the invention (the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.

The pharmaceutical preparations of the present invention may include or be diluted into a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” as used herein means one or more compatible fillers, diluents or other such substances, which are suitable for administration to a human or other mammal, such as a dog, cat, rat, mouse, or horse. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The carriers are capable of being commingled with the preparations of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy or stability. Carriers suitable for oral, subcutaneous, intravenous, intramuscular, etc. formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.

The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

In certain embodiments, the compound of the invention is administered at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

The present invention is further illustrated by the following Example, which in no way should be construed as further limiting. The entire contents of all of the references (including literature references, issued patents, published patent applications, and co pending patent applications) cited throughout this application are hereby expressly incorporated by reference.

EXAMPLES

In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Example 1 Preparation of the Compounds Preparation of I-11

4-methyl-3-((7-((2-(trimethylsilyflethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzoic acid: 4-chloro-74(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (284 mg, 1.0 mmol), 3-hydroxy-4-methylbenzoic acid (152 mg, 1.0 mmol) and K₂CO₃ (414 mg, 3.0 mmol) were combined in DMSO (5 mL) and stirred overnight at 100° C. The reaction mixture was then cooled to room temperature. The mixture was acidified with 1N HCl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography to yield 296 mg of product as a colorless oil. MS (ESI) m/z 400 (M+H)⁺.

3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(3-(2-cyanopropan-2-yl)phenyl)-4-methylbenzamide (I-11): To a solution of 4-methyl-3-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzoic acid (200 mg, 0.5 mmol), HATU (230 mg, 0.6 mmol), DMAP (73 mg, 0.6 mmol) and iPr₂NEt (220 uL, 1.25 mmol) in CH₂Cl₂ (3 mL) was added 2-(3-aminophenyl)-2-methylpropanenitrile (80 mg, 0.5 mmol) and the resulting mixture was stirred at room temperature for 24 hours. The solution was filtered to remove solids, concentrated and purified with column chromatography (dichloromethane:methanol=10:1) to afford 455 mg of product as a colorless oil. To the solution of the obtained oil in CH₂Cl₂ (5 mL) was added TFA (0.5 mL) and the resulting mixture was stirred at room temperature for 5 hours. The solution was concentrated and dried with vacuum, then dissolved in THF (4 mL) and 1 N NaOH solution (4 mL). The reaction mixture was stirred for 24 h and extracted with ethyl acetate. The combined organic phase was washed with brine and dried with Na₂SO₄, then filtered and concentrated, and purified by reverse phase HPLC to give 185 mg (90%) of title compound as a white solid.

Preparation of A-17

3-((6-chloropyrimidin-4-yl)oxy)-4-methylbenzoic acid: Sodium hydroxide (2 ml of a 1N solution) was added to a solution of 4,6-dichloropyrimidine (150 mg, 1.0 mmol) and 3-hydroxy-4-methylbenzoic acid (152 mg, 1.0 mmol) in acetone (2 mL) and the reaction mixture as stirred at room temperature for 1 hour at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with brine and dried with Na₂SO₄, then filtered and concentrated, and purified by column chromatography to yield 250 mg of product as a white solid. MS (ESI) m/z 265 (M+H)⁺.

3-((6-chloropyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide: To a solution of 3-((6-chloropyrimidin-4-yl)oxy)-4-methylbenzoic acid (210 mg, 0.8 mmol), HATU (365 mg, 0.96 mmol), DMAP (117 mg, 0.96 mmol) and iPr₂NEt (350 uL, 2.0 mmol) in CH₂Cl₂ (4 mL) was added 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (230 mg, 0.8 mmol) and the resulting mixture was stirred at room temperature for 24 hours. The solution was filtered to remove solids, concentrated and purified column chromatography to yield 360 mg (84%) of product as a pale yellow oil. MS (ESI) m/z 534 (M+H)⁺.

3-((6-aminopyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide: 10 mL of a 2N solution of NH₃ in i-PrOH was added to 3-((6-chloropyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (270 mg, 0.5 mmol) and the reaction mixture was stirred for 48 hours at 75° C. then cooled to room temperature and concentrated. The crude product was purified by column chromatography to yield 120 mg of product as a colorless oil. MS (ESI) m/z 515 (M+H)⁺.

3-((6-acrylamidopyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (A-17): To a solution of 3-((6-aminopyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (51 mg, 0.1 mmol) in DMF cooled in a dry ice/SOLVENT bath was added acryloyl chloride (8.9 uL, 0.11 mmol). The cooling bath was removed allowing the mixture to warm to room temperature and continue stirring for an half hour. The solution was then diluted in DMSO and purified by reverse phase HPLC to afford 45 mg (80%) of A-17 as a white solid.

Compounds (A-1)-(A-16) and (A-18) were prepared similarly to A-17.

Characterization data for all final compounds is in the table below.

ID # Structure Name ¹H NMR and or MS (m/z) A-1 

N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methyl-3-((6- (methylamino)pyrimidin- 4-yl)oxy)benzamide ¹H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 8.11 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.33 (bs, 1H), 3.60 (s, 2H), 3.38 (m, 2H), 2.97-2.79 (m, 6H), 2.71 (bs, 3H), 2.37-2.22 (m, 2H), 2.09 (s, 3H), 1.12 (t, J = 6.8 Hz, 3H). MS (ESI) m/z 529 (M + H)⁺. A-2 

N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methyl-3-((6- propionamidopyrimidin- 4-yl)oxy)benzamide ¹H NMR (600 MHz, TFA salt, DMSO) δ 10.89 (s, 1H), 10.42 (s, 1H), 9.36 (br, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.57 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 3.61 (s, 2H), 3.38 (m, 2H), 3.07 (m, 2H), 2.92 (m, 2H), 2.85 (m, 2H), 2.37 (q, J = 7.2 Hz, 2H), 2.32 (m, 2H), 2.10 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 571 (M + H)⁺. A-3 

3-((6- (cyclopropanecarboxamido) pyrimidin-4- yl)oxy)-N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methylbenzamide ¹H NMR (600 MHz, DMSO) δ 11.25 (s, 1H), 10.36 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 3.49 (s, 2H), 2.32 (m, 8H), 2.24 (m, 2H), 2.09 (s, 3H), 1.97 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H), 0.79 (m, 4H). MS (ESI) m/z 583 (M + H)⁺. A-4 

3-((6-aminopyrimidin- 4-yl)oxy)-N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methylbenzamide ¹H NMR (600 MHz, TFA salt, DMSO) δ 8.06 (s, 1H), 8.03 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.43 (d, J = 7.2 Hz, 1H), 5.78 (s, 1H), 3.70 (s, 2H), 3.47 (m, 2H), 3.15 (q, J = 7.2 Hz, 2H), 3.01 (m, 4H), 2.42 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 515 (M + H)⁺. A-5 

N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methyl-3-((6-((1- methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)oxy)benzamide ¹H NMR (600 MHz, DMSO) δ 10.36 (s, 1H), 9.37 (br, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 5.94 (s, 1H), 3.74 (s, 3H), 3.50 (s, 2H), 2.18-2.42 (m, 10H), 2.12 (s, 3H), 0.92 (m, 3H). MS (ESI) m/z 595 (M + H)⁺. A-6 

3-((6-((1H-pyrazol-5- yl)amino)pyrimidin-4- yl)oxy)-N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methylbenzamide ¹H NMR (600 MHz, TFA salt, DMSO) δ 10.45 (s, 1H), 9.92 (s, 1H), 9.33 (br, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 3.66 (s, 2H), 3.44 (m, 2H), 3.12 (m, 2H), 2.97 (m, 2H), 2.91 (m, 2H), 2.37 (m, 2H), 2.17 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). MS (ESI) w/z 581 (M + H)⁺. A-7 

3-((6-((1H-pyrazol-4- yl)amino)pyrimidin-4- yl)oxy)-N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methylbenzamide ¹H NMR (600 MHz, DMSO) δ 12.63 (br, 1H), 10.44 (s, 1H), 9.42 (br, 1H), 8.26 (br, 1H), 8.19 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.90 (br, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.53 (br, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.00 (s, 1H), 3.60 (s, 2H), 2.25-2.86 (m, 10H), 2.19 (s, 3H), 1.05 (m, 3H). MS (ESI) m/z 581 (M + H)⁺. A-8 

N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methyl-3-((6- (pyrimidin-5- ylamino)pyrimidin-4- yl)oxy)benzamide ¹H NMR (600 MHz, TFA salt, DMSO) δ 10.49 (s, 1H), 10.02 (s, 1H), 9.44 (br, 1H), 9.08 (s, 2H), 8.82 (s, 1H), 8.42 (s, 1H), 8.19 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 3.66 (s, 2H), 3.44 (m, 2H), 3.13 (m, 2H), 2.98 (m, 2H), 2.91 (m, 2H), 2.38 (m, 2H), 2.20 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 593 (M + H)⁺. A-9 

3-((6-(2- acetylhydrazinyl) pyrimidin-4-yl)oxy)-N-(4- ((4-ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methylbenzamide ¹H NMR (600 MHz, DMSO) δ 10.43 (s, 1H), 9.88 (s, 1H), 9.20 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 5.99 (s, 1H), 3.56 (s, 2H), 3.32 (m, 4H), 2.29-2.48 (m, 4H), 2.32 (q, J = 7.2 Hz, 2H), 2.17 (s, 3H), 1.92 (s, 3H), 0.97 (J = 7.2 Hz, 3H). MS (ESI) m/z 572 (M + H)⁺. A-10

3-((6-(azetidin-3- ylamino)pyrimidin-4- yl)oxy)-N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methylbenzamide ¹H NMR (600 MHz, TFA salt, DMSO) δ 10.56 (s, 1H), 10.05 (s, 1H), 9.47 (br, 1H), 8.76 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 6.35 (s, 1H), 4.60 (m, 1H), 4.38 (m, 2H), 3.68 (s, 2H), 3.57 (m, 2H), 3.46 (m, 2H), 3.12 (m, 2H), 2.98 (m, 2H), 2.92 (m, 2H), 2.39 (m, 2H), 2.21 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 570 (M + H)⁺. A-11

3-((6-(2,2- dimethylhydrazinyl) pyrimidin-4-yl)oxy)-N- (4-((4-ethylpiperazin- 1-yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methylhenzamide ¹H NMR (600 MHz, TFA salt, DMSO) δ 10.58 (s, 1H), 9.48 (br, 1H), 8.95 (s, 1H), 8.20 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.84 (br, 2H), 3.71 (s, 6H), 3.68 (s, 2H), 3.46 (m, 2H), 3.15 (m, 2H), 2.98 (m, 2H), 2.92 (m, 2H), 2.39 (m, 2H), 2.21 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 558 (M + H)⁺. A-12

N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methyl-3-((6-((1- methyl-1H-pyrazol-3- yl)amino)pyrimidin-4- yl)oxy)benzamide ¹H NMR (600 MHz, TFA salt, DMSO) δ 10.47 (s, 1H), 9.94 (s, 1H), 9.36 (br, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 6.16 (br, 1H), 3.75 (s, 3H), 3.68 (s, 2H), 3.45 (m, 2H), 3.14 (m, 2H), 2.99 (m, 2H), 2.94 (m, 2H), 2.37 (m, 2H), 2.19 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 595 (M + H)⁺. A-13

N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methyl-3-((6- (oxetan-3- ylamino)pyrimidin-4- yl)oxy)benzamide ¹H NMR (600 MHz, TFA salt, DMSO) δ 10.46 (s, 1H), 9.32 (br, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 8.15 (br, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 6.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 5.88 (br, 1H), 4.15 (m, 2H), 3.70 (m, 2H), 3.68 (s, 2H), 3.46 (m, 2H), 3.14 (m, 2H), 2.99 (m, 2H), 2.93 (m, 2H), 2.38 (m, 2H), 2.17 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 571 (M + H)⁺. A-14

N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methyl-3-((2-((1- methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)oxy)benzamide ¹H NMR (600 MHz, DMSO) δ 10.45 (s, 1H), 9.60 (br, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.98 (m, 1H), 7.88 (m, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.61 (m, 1H), 7.05 (m, 1H), 6.73 (m, 1H), 6.46 (m ,1H), 3.55 (s, 3H), 3.49 (br, 2H), 2.20-2.58 (m, 10H), 2.18 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 595 (M + H)⁺. A-15

N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 3-((2-(isoxazol-4- ylamino)pyrimidin-4- yl)oxy)-4- methylbenzamide ¹H NMR (600 MHz, TFA salt, DMSO) δ 10.51 (s, 1H), 9.90 (m, 1H), 9.31 (br, 1H), 8.44 (d, J = 5.4 Hz, 1H), 8.32 (m, 1H), 8.20 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.97 (m, 1H), 7.87 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 6.62 (s, 1H), 3.69 (s, 2H), 3.46 (m, 2H), 3.15 (m, 2H), 2.99 (m, 2H), 2.94 (m, 2H), 2.39 (m, 2H), 2.19 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 582 (M + H)⁺. A-16

N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 3-((6-(isoxazol-4- ylamino)pyrimidin-4- yl)oxy)-4- methylbenzamide MS (ESI) m/z 582 (M + H)+. A-17

3-((6- acrylamidopyrimidin- 4-yl)oxy)-N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methylbenzamide ¹H NMR (600 MHz, DMSO) δ 11.16 (s, 1H), 10.37 (s, 1H), 8.46 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 6.54 (dd, J = 16.8, 10.8 Hz, 1H), 6.30 (d, J = 16.8 Hz, 1H), 5.81 (d, J = 10.8 Hz, 1H), 3.49 (s, 2H), 2.32 (m, 8H), 2.23 (q, J = 7.2 Hz, 2H), 2.11 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 569 (M + H)⁺.  I-11

3-((7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)- N-(3-(2-cyanopropan- 2-yl)phenyl)-4- methylbenzamide ¹H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 8.22 (s, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.33 (dd, J = 8.0, 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 3.2 Hz, 1H), 2.10 (s, 3H), 1.61 (s, 6H). MS (ESI) m/z 412 (M + H)⁺.

Example 2 Biological Assays of the Compounds In Vitro Activity Assays

The in vitro activity of the compounds described herein in inhibiting TAK1, HCK and other kinases were obtained using an Invitrogen Select Screening assay as known in the art. The IC50 values determined from this assay are shown below.

Cell Proliferation Analysis

CellTiter-Glo® Luminescent cell viability assay (Promega) was used to assess cell survival following treatment with the compounds described. Cells were seeded into 384 well plates with the EL406 Combination Washer Dispenser (BioTek Instruments, Inc.) and the compounds were injected into the cells culture media with the JANUS Automated Workstation (PerkinElmer Inc.). Cells were treated with a series diluted inhibitors (20˜0.04 μM) for 72 hours at 37° C. Luminescent measurement is performed using the 2104 Envision® Multilabel Reader (PerkinElmer Inc.).

Apoptosis Analysis for Primary Patient Bone Marrow Tumor Cells

WM cells were treated with and without the compounds described herein. Cells were incubated at 37° C. with 0.01˜4 uM of the compounds described herein. Apoptosis analysis was performed using Annexin V/Propidium iodide staining with the Apoptosis Detection Kit I (BD Pharmingen). 1×106/well cells were treated in 24 well plates for ˜24 hours with inhibitors or corresponding controls. A minimum of 10,000 events were acquired using a BD™ FACSCanto II flow cytometer and analyzed with BD FACS DIVA Software.

Results

A number of compounds described herein show inhibitory activity against TAK1, HCK, BTK and other kinases. Shown in Table 1 and la are exemplary in vitro IC₅₀ data of these compounds. Table 2 and 2a shows the in vitro EC₅₀ values of these compounds.

TABLE 1 Compound BTK HCK IC₅₀ TAK1 GCK Structure ID IC₅₀ (nM) (nM) Inv IC₅₀ (nM) IC₅₀ (nM)

(A-1)  — 275 364 31

(A-17) 3380  28  45 17

(A-2)  — 253 100 28

(A-3)  — 185  92 —

(A-4)  — 382 591 —

 (I-11) — — — —

TABLE 1a BTK IC₅₀ HCK IC₅₀ TAK1 IC₅₀ Structure Cpd. ID (nM) (nM) Inv (nM)

(A-5)  >10000   61.8   100

(A-6)  —   38.4   63.5

(A-7)  —   33.8   71.7

(A-8)  —   889   487

(A-9)  — >10000  7310

(A-10) — >10000 >10000

(A-18) —  6980  1750

(A-11) — >10000 >10000

(A-12) —   18   76.2

(A-13) —   392   400

(A-14) —   27.4   53.8

(A-15) —   116 136

(A-16) — — —

TABLE 2 BCWM.1 MWCL-1 RPCIWM-1 OCI-Ly3 Ramos OCI-Ly19 Mec1 EC₅₀ Cpd. ID EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) (nM) (A-1) 1720 3990 — 11500 9480 4980 — (A-2) 42 1350 — 2960 5340 1750 — (A-3) 50 910 — 480 2680 600 — (A-4) 3010 1150 — 31900 21100 9430 14300 (A-17) 8 202 — 247 389 188 —

TABLE 2a BCWM.1 MWCL-1 TMD8 OCI-Ly7 OCI-Ly3 Ramos OCI-Ly19 Cpd. ID EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) EC₅₀ (nM) (A-5) 51 73 132 655 4710 3000 173 72 242 6060 417 (A-6) 86 118 — — 4770 3080 302 (A-7) 48 71 — — 4000 3020 192 (A-8) 980 2660 — — >10000 6180 1700 (A-9) 10800 18700 — — 19600 >20000 >20000 6460 >20000 >20000 (A-10) 8250 24800 — — 8370 >20000 >20000 >20000 >20000 >20000 (A-11) 19700 >20000 — — >20000 >20000 >20000 (A-12) 38 75 — — 156 2960 209 71 71 472 (A-13) 361 1760 — — 1200 3260 2280 964 2860 1730 (A-14) 33 128  45 173 — 2090 179 (A-15) 185 718 392 786 — 4680 307 (A-16) 610 1710 856 1030  — 1310 777 (A-18) 1980 4090 — — 1860 7240 2780 3750 6740 5030 (I-11) 4950 1440 3460  1120  9690 3890 —

Kinome Scan

Compounds (A-2) and (A-17) were run in the Kinome Scan™ (DiscoverRx) assay to determine the inhibition against a broad panel of known kinases.

Results

Table 3 shows the KinomeScan (an active site-directed competition binding assay to measure interactions between test compounds and individual kinases) data of each compound, II-1 and I-13. Lower values indicate a greater inhibition for a given kinase by the test compound. As is shown, II-1 and I-13 inhibited several other kinases include LOK, DDR1, JNK2, ZAK, IKK-alpha, BLK, p38-alpha, ABL1, LYN, and STK36 along with the key target HCK.

TABLE 3 Kinases A-2 (1 μM) A-17 (1 μM) TAOK1 0.45 0.05 LOK 0.05 0.1 TAOK3 0.45 0.1 DDR1 0.35 0.25 HCK 1.5 0.3 JNK2 0.15 0.3 ZAK 1.6 0.4 IKK-alpha 13 0.55 BLK 0.65 0.6 p38-alpha 0 0.75 ABL1-nonphosphorylated 1 0.8 LYN 3.6 0.8 STK36 1 0.9 LCK 1.6 1 FLT3 1.8 1.2 MKK7 11 1.2 MAP4K2 2.8 1.4 p38-beta 1.8 2.1 PDGFRB 5.1 2.5 CSF1R 3.2 2.6 RET(M918T) 7.4 2.8 ABL2 2.9 2.9 ABL1(E255K)-phosphorylated 3.3 3 CDC2L1 0.45 3.2 EPHA8 5.4 3.6 RET 9.9 3.6 CDC2L2 0.4 3.8 KIT(L576P) 2.2 3.9 CDK8 12 4 MAP4K4 6.4 4 KIT(V559D) 3.4 4.2 MINK 18 4.6 MAP3K3 21 4.8 TAOK2 0.15 4.8 JAK3(JH1domain-catalytic) 47 4.9 JNK1 6.8 5 KIT 5.6 5.1 FES 4.1 5.2 CDKL2 1.4 5.5 TIE1 5.5 5.5 ULK3 71 6 HPK1 30 6.2 CDK11 1.6 6.6 CDKL3 1.6 6.8 FGR 13 7.7 TNIK 20 9 CDC2L5 19 10 MST3 36 10 ABL1(M351T)-phosphorylated 6 11 DDR2 3 11 FGFR1 21 12 FLT3(N841I) 14 12 HIPK2 29 12 NLK 29 12 SRC 5.9 12 HIPK3 13 13 MAP4K5 29 14 p38-gamma 6.6 14 RSK2(Kin.Dom.2-C-terminal) 97 15 KIT(A829P) 32 16 KIT(V559D, T670I) 11 16 OSR1 79 16 TNK1 33 16 EPHB2 69 17 YSK1 21 17 EGFR(L747-E749del, A750P) 21 18 EPHA3 32 18 FRK 19 18 MST4 38 18 PCTK1 45 18 RET(V804M) 26 18 TIE2 13 18 PCTK2 10 20 ULK1 100 20 FGFR4 32 21 BRAF(V600E) 23 22 HIPK1 32 22 EGFR(L747-S752del, P753S) 19 23 FLT3(D835Y) 23 23 JNK3 15 23 p38-delta 15 23 FLT3(D835H) 23 24 CAMK1 38 26 CTK 40 26 FLT1 38 26 MYO3A 59 26 SGK3 97 26 YES 24 27 FGFR2 34 28 NEK4 59 30 SBK1 89 31 ABL1(F317L)-phosphorylated 3.9 33 AURKA 95 33 MEK3 84 33 CAMK1D 73 34 HIPK4 14 34 ZAP70 69 35 MUSK 43 37 ASK2 65 38 EGFR(E746-A750del) 28 38 FLT4 54 38 STK39 23 38 TTK 39 38 FLT3(R834Q) 64 39 PAK3 61 39 SLK 17 39 ABL1(T315I)-phosphorylated 37 40 CDK3 58 40 CSK 69 40 PFTK1 27 40 BRAF 42 41 FER 30 42 IKK-beta 48 42 PIK3CA(Q546K) 85 42 ABL1(T315I)-nonphosphorylated 0 44 MYLK2 63 44 PRKCD 39 44 ROCK1 97 44 CDKL1 45 45 TYK2(JH1domain-catalytic) 90 45 GRK7 68 46 PLK4 78 46 ROCK2 100 46 CDK2 43 47 MAST1 59 47 ABL1(F317I)-nonphosphorylated 0 48 EIF2AK1 62 48 AURKB 77 50 MEK6 77 50 ERBB2 46 51 ERN1 58 51 RET(V804L) 62 51 RPS6KA5(Kin.Dom.1-N-terminal) 78 51 KIT(V559D, V654A) 50 52 PCTK3 32 52 EGFR(L747-T751del, Sins) 18 53 EPHA2 40 53 EGFR(L861Q) 56 54 MAP3K15 100 54 SGK 100 54 FYN 52 55 PDGFRA 25 55 PIK3CA(C420R) 100 55 SRMS 66 55 CDK5 67 56 IRAK1 97 56 PIK3C2G 81 56 PKNB(M. tuberculosis) 100 56 QSK 69 56 YSK4 89 57 CIT 56 58 EGFR(T790M) 83 58 JAK2(JH1domain-catalytic) 74 58 MAP3K1 60 58 PIK3CA(E545A) 89 58 PIK3CG 94 58 NDR1 87 59 PFPK5(P. falciparum) 100 59 SRPK1 70 59 DYRK2 99 60 EGFR 55 60 GSK3A 40 60 ABL1(F317L)-nonphosphorylated 0 61 CLK1 85 61 PRKCQ 55 61 PAK1 96 62 STK35 80 62 ABL1(F317I)-phosphorylated 7.9 63 CAMK1G 61 64 CAMK4 100 64 CDKL5 93 64 CDK7 33 66 PLK3 100 66 PRKD1 87 66 IRAK4 99 67 PIK3CA(E545K) 88 67 EGFR(S752-I759del) 37 68 INSRR 71 68 PFTAIRE2 100 68 MYLK 100 69 PIK3CA(I800L) 83 70 SYK 21 70 AURKC 100 71 CASK 60 71 CDK9 46 71 CSNK1A1 83 71 EPHB6 92 71 PIK3CA 100 71 BMPR1B 99 72 FLT3-autoinhibited 68 72 PIK3CA(E542K) 87 72 PRKCI 65 73 ANKK1 100 74 EPHA4 64 75 EGFR(G719C) 60 76 EPHA5 86 76 JAK1(JH1domain-catalytic) 86 76 MST2 82 76 PRKCH 94 76 ARK5 96 77 CLK4 66 77 FGFR3 80 77 GAK 77 77 MEK1 100 77 MYO3B 76 77 WNK3 95 77 DCAMKL1 77 78 EPHA6 68 78 FGFR3(G697C) 81 78 KIT(D816H) 82 78 RIPK5 90 78 SNRK 68 78 ERBB4 88 79 EGFR(L858R) 83 80 IKK-epsilon 100 80 TLK1 100 80 TRKC 100 80 ERK2 100 81 PRKD2 73 81 ACVRL1 83 82 BMPR2 86 82 NEK10 100 82 PAK2 78 82 S6K1 54 82 SIK 73 82 GSK3B 83 83 HUNK 100 83 MERTK 100 83 NIK 62 83 PIP5K2B 100 83 RIOK1 100 83 VRK2 96 83 CAMK2D 92 84 PAK6 100 84 TBK1 95 84 GCN2(Kin.Dom.2, S808G) 84 85 PKN1 100 85 SGK2 100 85 TGFBR2 100 85 WNK1 100 85 ALK 92 86 DCAMKL3 97 86 MEK2 83 86 PIM1 100 86 PRKCE 92 86 TAK1 3.2 86 YANK2 100 86 AXL 68 87 MKNK2 72 87 NEK6 91 87 PIP5K1A 100 87 ADCK3 100 88 CLK2 100 88 ERK8 100 88 PIK3CB 66 88 PIM3 93 88 RAF1 75 88 AKT1 82 89 BUB1 80 89 MAP4K3 100 89 BTK 65 90 ICK 65 90 PAK7 100 90 PIK3CD 100 90 RIOK3 83 90 BMX 79 91 CDK4-cyclinD1 94 91 SNARK 100 91 TRKA 90 91 ALK(L1196M) 90 92 LATS2 100 92 PRKG2 74 92 NEK2 98 93 TRKB 85 93 AAK1 94 94 EGFR(L858R, T790M) 80 94 ERK3 93 94 LRRK2(G2019S) 100 94 PAK4 95 94 PIK3CA(H1047L) 97 94 RIPK4 88 94 RPS6KA4(Kin.Dom.1-N-terminal) 96 94 TESK1 81 94 CSF1R-autoinhibited 96 95 LIMK2 94 95 LRRK2 95 95 PIK3CA(M1043I) 83 95 RPS6KA4(Kin.Dom.2-C-terminal) 100 95 TNNI3K 64 95 HASPIN 84 96 MAP3K4 80 96 PRP4 94 96 YANK1 73 96 ABL1(Y253F)-phosphorylated 4.8 97 EGFR(G719S) 65 97 MLK1 91 97 NEK1 93 97 PIK4CB 98 97 BIKE 92 98 RSK2(Kin.Dom.1-N-terminal) 100 98 SRPK2 100 98 STK16 100 98 AMPK-alpha2 95 99 CAMKK2 79 99 EPHB4 87 99 RSK4(Kin.Dom.1-N-terminal) 92 99 ABL1(Q252H)-phosphorylated 11 100 ACVR1 100 100 ACVR1B 100 100 ACVR2A 100 100 ACVR2B 95 100 ADCK4 100 100 AKT2 90 100 AKT3 100 100 ALK(C1156Y) 49 100 AMPK-alpha1 85 100 ASK1 96 100 BMPR1A 100 100 BRK 100 100 BRSK1 100 100 BRSK2 100 100 CAMK2A 92 100 CAMK2B 100 100 CAMK2G 86 100 CAMKK1 100 100 CDK4-cyclinD3 100 100 CHEK1 100 100 CHEK2 100 100 CLK3 100 100 CSNK1A1L 99 100 CSNK1D 100 100 CSNK1E 100 100 CSNK1G1 100 100 CSNK1G2 100 100 CSNK1G3 93 100 CSNK2A1 100 100 CSNK2A2 100 100 DAPK1 100 100 DAPK2 93 100 DAPK3 100 100 DCAMKL2 74 100 DLK 100 100 DMPK 100 100 DMPK2 88 100 DRAK1 100 100 DRAK2 85 100 DYRK1A 92 100 DYRK1B 77 100 EPHA1 90 100 EPHA7 75 100 EPHB1 78 100 EPHB3 100 100 ERBB3 100 100 ERK1 100 100 ERK4 96 100 ERK5 98 100 FAK 100 100 GRK1 77 100 GRK4 100 100 IGF1R 100 100 INSR 100 100 IRAK3 100 100 ITK 95 100 JAK1(JH2domain-pseudokinase) 90 100 KIT(D816V) 96 100 KIT-autoinhibited 65 100 LATS1 100 100 LIMK1 100 100 LKB1 100 100 LTK 100 100 LZK 100 100 MAK 93 100 MAP3K2 90 100 MAPKAPK2 100 100 MAPKAPK5 94 100 MARK1 83 100 MARK2 100 100 MARK3 94 100 MARK4 92 100 MEK4 82 100 MEK5 37 100 MELK 89 100 MET 100 100 MET(M1250T) 89 100 MET(Y1235D) 100 100 MKNK1 94 100 MLCK 100 100 MLK2 100 100 MLK3 62 100 MRCKA 100 100 MRCKB 100 100 MST1 80 100 MST1R 100 100 MTOR 86 100 MYLK4 100 100 NDR2 100 100 NEK11 100 100 NEK3 65 100 NEK5 85 100 NEK7 100 100 NEK9 100 100 NIM1 100 100 PDPK1 69 100 PHKG1 100 100 PHKG2 100 100 PIK3C2B 100 100 PIK3CA(H1047Y) 79 100 PIM2 71 100 PIP5K1C 50 100 PIP5K2C 82 100 PKAC-alpha 72 100 PKAC-beta 100 100 PKMYT1 100 100 PKN2 89 100 PLK1 100 100 PLK2 100 100 PRKD3 100 100 PRKG1 100 100 PRKR 100 100 PRKX 100 100 PYK2 97 100 RIOK2 100 100 RIPK1 54 100 RIPK2 86 100 ROS1 75 100 RPS6KA5(Kin.Dom.2-C-terminal) 100 100 RSK1(Kin.Dom.1-N-terminal) 100 100 RSK1(Kin.Dom.2-C-terminal) 100 100 RSK3(Kin.Dom.1-N-terminal) 100 100 RSK3(Kin.Dom.2-C-terminal) 100 100 RSK4(Kin.Dom.2-C-terminal) 100 100 SgK110 100 100 SIK2 100 100 SRPK3 100 100 STK33 97 100 TEC 82 100 TGFBR1 100 100 TLK2 100 100 TNK2 100 100 TRPM6 58 100 TSSK1B 83 100 TXK 89 100 TYK2(JH2domain-pseudokinase) 87 100 TYRO3 92 100 ULK2 81 100 VEGFR2 28 100 WEE1 100 100 WEE2 100 100 YANK3 88 100

Kinative

The kinase selectivity of compounds (A-5) and (A-14) were evaluated using a chemical proteomic approach named KiNativ which detects 260 kinases in A375 cells (ActivX Biosciences). To probe the intracellular targets of the compounds, A375 cells were incubated with the inhibitor at 1 μM final concentration and then looked for protection of labeling by an ATP-biotin probe that non-specifically labels conserved lysines on kinases and other nucleotide-dependent enzymes.

Results

Table 4 shows that compound (A-5) inhibits a number of kinases at 1 μM, including Abl (>90%), FYN (71.2%), LYN (87.8%), and ZAK (75.7%). Table 5 shows that compound (A-14) inhibits a number of kinases at 1 μM, including Abl (>90%), FYN (88.2%), LYN (85.7%), and ZAK (75.8%).

TABLE 4 SEQ ID Compound A-4 Kinase Reference Sequence NO: Labeling Site (1.0 μM) ABL, ARG UniRef100_P00519, LMTGDTYTAHAGAKFPIK 1 Activation 95.5 UniRef100_P42684 Loop ACK UniRef100_Q07912 TVSVAVKCLKPDVLSQPEA 2 Lys1 4.9 MDDFIR AGK UniRef100_Q53H12 ATVFLNPAACKGK 3 ATP −31.4 AMPKa1, UniRef100_P54646, DLKPENVLLDAHMNAK 4 Lys2 16.3 AMPKa2 UniRef100_Q13131 ARAF UniRef100_P10398 DLKSNNIFLHEGLTVK 5 Lys2 12.2 ATR UniRef100_Q13535 FYIMMCKPK 6 ATP 23.0 AurA UniRef100_O14965 FILALKVLFK 7 Lys1 −16.0 AurB UniRef100_Q96GD4 SHFIVALKVLFK 8 Lys1 −51.1 BARK1 UniRef100_P25098 DLKPANILLDEHGHVR 9 Lys2 −13.4 BRAF UniRef100_P15056 DLKSNNIFLHEDLTVK 10 Lys2 18.9 BTK UniRef100_Q06187 YVLDDEYTSSVGSKFPVR 11 Activation −18.8 Loop CaMK1a UniRef100_Q14012 LVAIKCIAK 12 Lys1 12.4 CaMK1d UniRef100_Q8IU85 LFAVKCIPK 13 Lys1 −6.0 CaMK2d UniRef100_Q13557 IPTGQEYAAKIINTKK 14 Lys1 −8.1 CaMK2g UniRef100_Q13555 TSTQEYAAKIINTK 15 Lys1 −23.1 CaMK4 UniRef100_Q16566 DLKPENLLYATPAPDAPLK 16 Lys2 5.9 CaMKK2 UniRef100_Q96RR4 DIKPSNLLVGEDGHIK 17 Lys2 6.2 CASK UniRef100_O14936, ETGQQFAVKIVDVAK 18 Lys1 −28.1 UniRef100_C9JGY0 CDC2 UniRef100_P06493 DLKPQNLLIDDKGTIK 19 Lys2 −2.3 CDK11, UniRef100_P49336, DLKPANILVMGEGPER 20 Lys2 50.0 CDK8 UniRef100_Q9BWU1 CDK2 UniRef100_P24941 DLKPQNLLINTEGAIK 21 Lys2 −3.5 CDK4 UniRef100_P11802 DLKPENILVTSGGTVK 22 Lys2 17.4 CDK5 UniRef100_Q00535 DLKPQNLLINR 23 Lys2 −27.3 CDK6 UniRef100_Q00534 DLKPQNILVTSSGQIK 24 Lys2 13.1 CDK7 UniRef100_P50613 DLKPNNLLLDENGVLK 25 Lys2 3.9 CDK9 UniRef100_P50750 DMKAANVLITR 26 Lys2 −16.2 CHK1 UniRef100_B5BTY6, DIKPENLLLDER 27 Lys2 −5.0 UniRef100_O14757 CHK2 UniRef100_O96017 DLKPENVLLSSQEEDCLIK 28 Lys2 −7.8 CK1a UniRef100_P48729, DIKPDNFLMGIGR 29 Lys2 −0.6 UniRef100_B4E1D9 CK1g2 UniRef100_P78368 DVKPENFLVGRPGTK 30 Lys2 −9.1 CK2a2 UniRef100_P19784 DVKPHNVMIDHQQK 31 Lys2 −18.2 CLK3 UniRef100_P49761 YEIVGNLGEGTFGKVVECL 32 ATP Loop −52.8 DHAR CSK UniRef100_P41240 VSDFGLTKEASSTQDTGKL 33 Activation 15.3 PVK Loop DGKA UniRef100_P23743 IDPVPNTHPLLVFVNPKSG 34 ATP −4.8 GK DGKH UniRef100_Q86XP1 ATFSFCVSPLLVFVNSKSG 35 ATP −6.3 DNQGVK DGKQ UniRef100_P52824 GRLLTALVLPDLLHAKLPP 36 ATP 11.0 DSCPLLVFVNPKSGGLK DNAPK UniRef100_P78527 KGGSWIQEINVAEK 37 ATP −61.5 DNAPK UniRef100_P78527 EHPFLVKGGEDLR 38 ATP −64.6 eEF2K UniRef100_O00418 YIKYNSNSGFVR 39 ATP −30.5 EphB1 UniRef100_P54762 YLQDDTSDPTYTSSLGGKI 40 Activation −1.7 PVR Loop EphB2 UniRef100_P29323 FLEDDTSDPTYTSALGGKI 41 Activation −12.8 PIR Loop Erk1 UniRef100_P27361 DLKPSNLLINTTCDLK 42 Lys2 −9.0 Erk2 UniRef100_P28482 DLKPSNLLLNTTCDLK 43 Lys2 −3.8 Erk5 UniRef100_Q13164 DLKPSNLLVNENCELK 44 Lys2 25.9 FER UniRef100_P16591 TSVAVKTCKEDLPQELK 45 Lys1 91.4 FES UniRef100_P07332 LRADNTLVAVKSCR 46 Lys1 89.1 FGR UniRef100_P09769 LIKDDEYNPCQGSKFPIK 47 Activation 31.9 Loop FRAP UniRef100_P42345 IQSIAPSLQVITSKQRPR 48 ATP −7.5 FRK UniRef100_P42685 HEIKLPVK 49 Activation 91.1 Loop FYN, SRC, UniRef100_P12931, QGAKFPIKWTAPEAALYGR 50 Activation 71.2 YES UniRef100_P07947, Loop UniRef100_P06241 GCK UniRef100_Q12851 DIKGANLLLTLQGDVK 51 Lys2 94.9 GCN2 UniRef100_Q9P2K8 DLKPVNIFLDSDDHVK 52 Lys2 20.8 GSK3A UniRef100_P49840 DIKPQNLLVDPDTAVLK 53 Lys2 36.0 GSK3B UniRef100_P49841 DIKPQNLLLDPDTAVLK 54 Lys2 0.5 HPK1 UniRef100_Q92918 DIKGANILINDAGEVR 55 Lys2 68.1 IKKa UniRef100_O15111 DLKPENIVLQDVGGK 56 Lys2 −17.0 IKKb UniRef100_O14920 DLKPENIVLQQGEQR 57 Lys2 −12.6 IKKe UniRef100_Q14164 SGELVAVKVFNTTSYLRPR 58 Lys1 −9.9 ILK UniRef100_Q13418 WQGNDIVVKVLK 59 Lys1 5.2 IRAKI UniRef100_P51617 AIQFLHQDSPSLIHGDIKSS 60 Lys2 −3.5 NVLLDER IRAK4 UniRef100_Q9NWZ3 DIKSANILLDEAFTAK 61 Lys2 1.9 IRE1 UniRef100_O75460 DLKPHNILISMPNAHGK 62 Lys2 −2.2 ITPK1 UniRef100_Q13572 ESIFFNSHNVSKPESSSVLT 63 ATP 1.2 ELDKIEGVFERPSDEVIR JAK1 UniRef100_P23458 QLASALSYLEDKDLVHGN 64 Protein 4.3 VCTKNLLLAR Kinase Domain JAK1 UniRef100_P23458 IGDFGLTKAIETDKEYYTVK 65 Activation −6.2 domain2 Loop JAK3 UniRef100_P52333 IADFGLAKLLPLDKDYYVVR 66 Activation 7.7 domain2 Loop JNK1, UniRef100_P45983, DLKPSNIVVK 67 Lys2 77.2 JNK2, UniRef100_P53779, JNK3 UniRef100_P45984 KHS1 UniRef100_Q9Y4K4 NVHTGELAAVKIIK 68 Lys1 15.8 KSR1 UniRef100_Q8IVT5 SKNVFYDNGKVVITDFGLF 69 Activation −22.0 GISGVVR Loop KSR1, UniRef100_Q6VAB6, SKNVFYDNGK 70 Activation −10.0 KSR2 UniRef100_Q8IVT5 Loop LATS1 UniRef100_O95835 ALYATKTLR 71 Lys1 5.4 LATS2 UniRef100_Q9NRM7 DIKPDNILIDLDGHIK 72 Lys2 −1.9 LCK UniRef100_P06239 EGAKFPIKWTAPEAINYGT 73 Activation 92.3 FTIK Loop LKB1 UniRef100_Q15831 DIKPGNLLLTTGGTLK 74 Lys2 −6.0 LOK UniRef100_O94804 DLKAGNVLMTLEGDIR 75 Lys2 19.9 LRRK2 UniRef100_Q5S007 DLKPHNVLLFTLYPNAAIIAK 76 Lys2 −15.9 LYN UniRef100_P07948 VAVKTLKPGTMSVQAFLE 77 Lys1 87.8 EANLMK MAP2K1 UniRef100_Q02750 IMHRDVKPSNILVNSR 78 Lys2 11.4 MAP2K1, UniRef100_P36507, DVKPSNILVNSR 79 Lys2 −16.3 MAP2K2 UniRef100_Q02750 MAP2K3 UniRef100_P46734 DVKPSNVLINK 80 Lys2 −1.0 MAP2K4 UniRef100_P45985 DIKPSNILLDR 81 Lys2 −14.1 MAP2K5 UniRef100_Q13163 DVKPSNMLVNTR 82 Lys2 20.5 MAP2K6 UniRef100_P52564 DVKPSNVLINALGQVK 83 Lys2 0.5 MAP2K7 UniRef100_O14733 DVKPSNILLDER 84 Lys2 −38.2 MAP3K1 UniRef100_Q13233 DVKGANLLIDSTGQR 85 Lys2 26.9 MAP3K2 UniRef100_Q9Y2U5 ELAVKQVQFDPDSPETSK 86 Lys1 4.2 EVNALECEIQLLK MAP3K2, UniRef100_Q9Y2U5, DIKGANILR 87 Lys2 3.2 MAP3K3 UniRef100_Q99759 MAP3K3 UniRef100_Q99759 ELASKQVQFDPDSPETSKE 88 Lys1 3.7 VSALECEIQLLK MAP3K4 UniRef100_Q9Y6R4 DIKGANIFLTSSGLIK 89 Lys2 19.2 MAP3K5 UniRef100_Q99683 DIKGDNVLINTYSGVLK 90 Lys2 −30.4 MAP3K6 UniRef100_O95382 DIKGDNVLINTFSGLLK 91 Lys2 −25.0 MARK2, UniRef100_P27448, DLKAENLLLDADMNIK 92 Lys2 4.6 MARK3 UniRef100_Q7KZI7 MARK3 UniRef100_P27448 EVAIKIIDKTQLNPTSLQK 93 Lys1 −26.1 MARK3, UniRef100_Q96L34, EVAIKIIDK 94 Lys1 −16.2 MARK4 UniRef100_P27448 MARK4 UniRef100_Q96L34 DLKAENLLLDAEANIK 95 Lys2 2.9 MAST1, UniRef100_Q6P0Q8, DLKPDNLLITSMGHIK 96 Lys2 35.6 MAST2 UniRef100_Q9Y2H9 MAST3 UniRef100_O60307 DLKPDNLLITSLGHIK 97 Lys2 −8.1 MASTL UniRef100_Q96GX5 GAFGKVYLGQK 98 ATP Loop 12.8 MASTL UniRef100_Q96GX5 LYAVKVVK 99 Lys1 3.3 MELK UniRef100_Q14680 DLKPENLLFDEYHK 100 Lys2 −19.6 MER UniRef100_Q12866 NCMLRDDMTVCVADFGL 101 Activation 49.8 SKK Loop MER, UniRef100_Q06418, KIYSGDYYR 102 Activation 1.6 TYRO3 UniRef100_Q12866 Loop MET UniRef100_P08581 DMYDKEYYSVHNK 103 Activation −21.0 Loop MLK3 UniRef100_Q16584 DLKSNNILLLQPIESDDME 104 Lys2 20.7 HK MLK4 UniRef100_Q5TCX8 DLKSSNILLLEK 105 Lys2 −1.7 MLKL UniRef100_Q8NB16 APVAIKVFK 106 Lys1 −14.9 MPSK1 UniRef100_O75716 DLKPTNILLGDEGQPVLM 107 Lys2 16.1 DLGSMNQACIHVEGSR MSK1 UniRef100_O75582 DIKLENILLDSNGHVVLTD 108 Lys2 5.7 domain1 FGLSK MSK2 UniRef100_O75676 DLKLENVLLDSEGHIVLTD 109 Lys2 −64.9 domain1 FGLSK MST1 UniRef100_Q13043 ETGQIVAIKQVPVESDLQE 110 Lys1 −4.7 IIK MST2 UniRef100_Q13188 ESGQVVAIKQVPVESDLQ 111 Lys1 −6.2 EIIK MST3 UniRef100_Q9Y6E0 DIKAANVLLSEHGEVK 112 Lys2 −3.7 MST4 UniRef100_Q9P289 TQQVVAIKIIDLEEAEDEIE 113 Lys1 6.2 DIQQEITVLSQCDSSYVTK MST4, UniRef100_O00506, DIKAANVLLSEQGDVK 114 Lys2 4.6 YSK1 UniRef100_Q9P289 MYO3A, UniRef100_Q8NEV4, DVKGNNILLTTEGGVK 115 Lys2 −15.3 MYO3B UniRef100_Q8WXR4 NDR1 UniRef100_Q15208 DIKPDNLLLDSK 116 Lys2 9.3 NDR2 UniRef100_Q9Y2H1 DIKPDNLLLDAK 117 Lys2 −10.9 NEK1 UniRef100_Q96PY6 DIKSQNIFLTK 118 Lys2 −3.0 NEK2 UniRef100_P51955 DLKPANVFLDGK 119 Lys2 −22.7 NEK3 UniRef100_P51956 SKNIFLTQNGK 120 Activation 13.1 Loop NEK4 UniRef100_P51957 DLKTQNVFLTR 121 Lys2 1.5 NEK6, UniRef100_Q8TDX7, DIKPANVFITATGVVK 122 Lys2 −12.5 NEK7 UniRef100_Q9HC98 NEK7 UniRef100_Q8TDX7 AACLLDGVPVALKK 123 Lys1 −7.2 NEK8 UniRef100_Q86SG6 DLKTQNILLDK 124 Lys2 −11.4 NEK9 UniRef100_Q8TD19 DIKTLNIFLTK 125 Lys2 −1.2 OSR1 UniRef100_C9JIG9, DVKAGNILLGEDGSVQIA 126 Lys2 −11.1 UniRef100_O95747 DFGVSAFLATGGDITR p38a UniRef100_Q16539 DLKPSNLAVNEDCELK 127 Lys2 61.4 p38a UniRef100_Q16539 QELNKTIWEVPER 128 Protein 92.2 Kinase Domain p38b UniRef100_Q15759 QELNKTVWEVPQR 129 Protein 51.4 Kinase Domain p38d, UniRef100_O15264, DLKPGNLAVNEDCELK 130 Lys2 62.5 p38g UniRef100_P53778 p70S6K UniRef100_P23443 DLKPENIMLNHQGHVK 131 Lys2 −2.3 p70S6Kb UniRef100_Q9UBS0 DLKPENIMLSSQGHIK 132 Lys2 8.2 PAN3 UniRef100_Q58A45 VMDPTKILITGK 133 ATP 12.1 PCTAIRE1 UniRef100_Q00536 SKLTDNLVALKEIR 134 Lys1 −3.5 PCTAIRE2, UniRef100_Q00537, SKLTENLVALKEIR 135 Lys1 11.7 PCTAIRE3 UniRef100_Q07002 PDK1 UniRef100_O15530 EYAIKILEK 136 Lys1 18.8 PEK UniRef100_Q9NZJ5 DLKPSNIFFTMDDVVK 137 Lys2 9.4 PFTAIRE1 UniRef100_O94921 LVALKVIR 138 Lys1 4.3 PHKg1 UniRef100_Q16816 DLKPENILLDDNMNIK 139 Protein −49.0 Kinase Domain PHKg2 UniRef100_P15735 ATGHEFAVKIMEVTAER 140 Lys1 15.2 PI4KA, UniRef100_A4QPH2, SGTPMQSAAKAPYLAK 141 ATP 19.3 PI4KAP2 UniRef100_P42356 PI4KB UniRef100_Q9UBF8 VPHTQAVVLNSKDK 142 ATP −0.2 PIK3C2B UniRef100_O00750 VIFKCGDDLRQDMLTLQ 143 ATP 24.0 MIR PIK3C3 UniRef100_Q8NEB9 TEDGGKYPVIFKHGDDLR 144 ATP −5.1 PIK3CB UniRef100_Q9BTS4, VFGEDSVGVIFKNGDDLR 145 ATP 27.8 UniRef100_P42338 QDMLTLQMLR PIK3CD UniRef100_O00329 VNWLAHNVSKDNRQ 146 ATP 2.2 PIK3CG UniRef100_P48736 KKPLWLEFK 147 ATP −21.1 PIP4K2A UniRef100_P48426 AKELPTLKDNDFINEGQK 148 ATP −26.7 PIP4K2B UniRef100_P78356 AKDLPTFKDNDFLNEGQK 149 ATP −44.7 PIP4K2C UniRef100_Q8TBX8 TLVIKEVSSEDIADMHSNL 150 ATP 5.2 SNYHQYIVK PIP5K3 UniRef100_Q9Y2I7 GGKSGAAFYATEDDRFILK 151 ATP 0.9 PITSLRE UniRef100_P21127 DLKTSNLLLSHAGILK 152 Lys2 −10.4 PKCa, UniRef100_P17252, DLKLDNVMLDSEGHIK 153 Lys2 2.3 PKCb UniRef100_P05771, UniRef100_B5BU22 PKD2 UniRef100_Q9BZL6 DVAVKVIDK 154 Lys1 −6.9 PKN1 UniRef100_Q16512 VLLSEFRPSGELFAIKALK 155 Lys1 −32.1 PKR UniRef100_P19525 DLKPSNIFLVDTK 156 Lys2 −28.4 PLK1 UniRef100_P53350 CFEISDADTKEVFAGKIVPK 157 Lys1 −9.1 PRP4 UniRef100_Q13523 CNILHADIKPDNILVNESK 158 Lys2 −20.1 PRPK UniRef100_Q96S44 FLSGLELVKQGAEAR 159 ATP Loop −13.7 PYK2 UniRef100_Q14289 YIEDEDYYKASVTR 160 Activation 10.9 Loop RAF1 UniRef100_P04049 DMKSNNIFLHEGLTVK 161 Lys2 36.6 RIPK3 UniRef100_Q9Y572 DLKPSNVLLDPELHVK 162 Lys2 32.6 ROCK1, UniRef100_O75116, DVKPDNMLLDK 163 Lys2 22.0 ROCK2 UniRef100_Q13464 RSK1 UniRef100_Q15418 DLKPENILLDEEGHIKLTDF 164 Lys2 −20.9 domain1 GLSKEAIDHEK RSK1 UniRef100_Q15418, DLKPENILLDEEGHIK 165 Lys2 −17.7 domain1, UniRef100_P51812, RSK2 UniRef100_Q15349 domain1, RSK3 domain1 RSK1 UniRef100_Q15418 DLKPSNILYVDESGNPECLR 166 Lys2 −16.3 domain2 RSK2 UniRef100_P51812 DLKPENILLDEEGHIKLTDF 167 Lys2 −3.3 domain1 GLSKESIDHEK RSK2 UniRef100_P51812 DLKPSNILYVDESGNPESIR 168 Lys2 −24.1 domain2 RSK3 UniRef100_Q15349 DLKPENILLDEEGHIKITDF 169 Lys2 −32.6 domain1 GLSK RSK4 UniRef100_Q9UK32 DLKPENILLDEIGHIK 170 Lys2 27.6 domain1 RSKL1 UniRef100_Q96S38 VLGVIDKVLLVMDTR 171 ATP 31.5 SGK3 UniRef100_Q96BR1 FYAVKVLQK 172 Lys1 −10.2 SLK UniRef100_Q9H2G2 DLKAGNILFTLDGDIK 173 Lys2 −14.3 SMG1 UniRef100_Q96Q15 DTVTIHSVGGTITILPTKTK 174 ATP −4.0 PK SNRK UniRef100_Q9NRH2 DLKPENVVFFEK 175 Lys2 18.0 SRC UniRef100_P12931 VAIKTLKPGTMSPEAFLQE 176 Lys1 76.1 AQVMKK SRPK1 UniRef100_Q96SB4 IIHTDIKPENILLSVNEQYIR 177 Lys2 −34.1 STK33 UniRef100_Q9BYT3 DLKLENIMVK 178 Lys2 12.9 STLK5 UniRef100_Q7RTN6 YSVKVLPWLSPEVLQQNL 179 Activation 5.0 QGYDAK Loop SYK UniRef100_P43405 ISDFGLSKALR 180 Activation 17.4 Loop TAK1 UniRef100_O43318 DLKPPNLLLVAGGTVLK 181 Lys2 32.0 TAO1, UniRef100_Q9H2K8, DIKAGNILLTEPGQVK 182 Lys2 76.5 TAO3 UniRef100_Q7L7X3 TAO2 UniRef100_Q9UL54 DVKAGNILLSEPGLVK 183 Lys2 86.0 TBK1 UniRef100_Q9UHD2 TGDLFAIKVFNNISFLRPV 184 Lys1 18.2 DVQMR TEC UniRef100_P42680 YVLDDQYTSSSGAKFPVK 185 Activation −12.8 Loop TLK1 UniRef100_Q9UKI8 YLNEIKPPIIHYDLKPGNILL 186 Lys2 4.9 VDGTACGEIK TLK2 UniRef100_Q86UE8 YLNEIKPPIIHYDLKPGNILL 187 Lys2 7.1 VNGTACGEIK TYK2 UniRef100_P29597 IGDFGLAKAVPEGHEYYR 188 Activation −18.1 domain2 Loop ULK1 UniRef100_O75385 DLKPQNILLSNPAGR 189 Lys2 −6.0 ULK3 UniRef100_D3DW67, NISHLDLKPQNILLSSLEKP 190 Lys2 −4.4 UniRef100_Q6PHR2 HLK VRK2 UniRef100_Q86Y07 MLDVLEYIHENEYVHGDIK 191 Lys2 27.9 AANLLLGYK Wee1 UniRef100_P30291 YIHSMSLVHMDIKPSNIFISR 192 Lys2 23.2 Wnk1, UniRef100_Q9Y3S1, GSFKTVYK 193 ATP Loop 24.2 Wnk2 UniRef100_D3DUP1, UniRef100_Q9H4A3 Wnk1, UniRef100_Q9Y351, DLKCDNIFITGPTGSVK 194 Lys2 0.2 Wnk2, UniRef100_D3DUP1, Wnk3 UniRef100_Q9BYP7, UniRef100_Q9H4A3 YANK3 UniRef100_Q86UX6 DVKPDNILLDER 195 Lys2 27.7 ZAK UniRef100_Q9NYL2 WISQDKEVAVKK 196 Lys1 75.7 ZAP70 UniRef100_P43403 ISDFGLSKALGADDSYYTAR 197 Activation 49.2 Loop ZC1/HGK, UniRef100_O95819, DIKGQNVLLTENAEVK 198 Lys2 19.2 ZC2/TNIK, UniRef100_Q9UKE5 ZC3/MINK UniRef100_Q8N4C8 ZC2/TNIK UniRef100_Q9UKE5 TGQLAAIKVMDVTGDEEE 199 Lys1 23.9 EIKQEINMLKK

TABLE 5 SEQ ID Kinase Reference Sequence NO: Labeling Site Cmpd. A-14 (1.0 μM) ABL, ARG UniRef100_P00519, LMTGDTYTAHAGAKFPIK 200 Activation 98.4 UniRef100_P42684 Loop ACK UniRef100_Q07912 TVSVAVKCLKPDVLSQPEA 201 Lys1 8.5 MDDFIR AGK UniRef100_Q53H12 ATVFLNPAACKGK 202 ATP 5.9 AKT1 UniRef100_P31749 GTFGKVILVK 203 ATP Loop −23.9 AKT2, UniRef100_Q9Y243, GTFGKVILVR 204 ATP Loop −19.7 AKT3 UniRef100_P31751 AMPKa1, UniRef100_P54646, DLKPENVLLDAHMNAK 205 Lys2 −17.5 AMPKa2 UniRef100_Q96E92 ANPa UniRef100_P16066 GMLFLHNGAICSHGNLKS 206 Lys2 −5.3 SNCVVDGR ARAF UniRef100_P10398 DLKSNNIFLHEGLTVK 207 Lys2 2.0 ATR UniRef100_Q13535 FYIMMCKPK 208 ATP −20.3 AurA UniRef100_O14965 FILALKVLFK 209 Lys1 14.6 AurA UniRef100_O14965 DIKPENLLLGSAGELK 210 Lys2 6.1 AurA, UniRef100_O14965, GKFGNVYLAR 211 ATP Loop −2.4 AurB, UniRef100_Q9UQB9, AurC UniRef100_Q96GD4 AurB UniRef100_Q96GD4 SHFIVALKVLFK 212 Lys1 3.3 BARK1 UniRef100_P25098 DLKPANILLDEHGHVR 213 Lys2 −13.6 BRAF UniRef100_P15056 DLKSNNIFLHEDLTVK 214 Lys2 18.9 BTK UniRef100_Q06187 YVLDDEYTSSVGSKFPVR 215 Activation −10.2 Loop CaMK1a UniRef100_Q14012 LVAIKCIAK 216 Lys1 −5.4 CaMK1d UniRef100_Q8IU85 LFAVKCIPK 217 Lys1 −1.8 CaMK2d UniRef100_Q13557 IPTGQEYAAKIINTKK 218 Lys1 −7.3 CaMK2g UniRef100_Q13555 TSTQEYAAKIINTK 219 Lys1 2.0 CaMK4 UniRef100_Q16566 DLKPENLLYATPAPDAPLK 220 Lys2 −2.0 CaMKK2 UniRef100_Q96RR4 DIKPSNLLVGEDGHIK 221 Lys2 16.2 CASK UniRef100_O14936 ETGQQFAVKIVDVAK 222 Lys1 7.1 CDC2 UniRef100_Q5H9N4 DLKPQNLLIDDKGTIK 223 Lys2 9.0 CDK11, UniRef100_P49336, DLKPANILVMGEGPER 224 Lys2 49.2 CDK8 UniRef100_Q9BWU1 CDK2 UniRef100_P24941 DLKPQNLLINTEGAIK 225 Lys2 34.5 CDK4 UniRef100_P11802 DLKPENILVTSGGTVK 226 Lys2 11.4 CDK5 UniRef100_Q00535 DLKPQNLLINR 227 Lys2 11.3 CDK6 UniRef100_Q00534 DLKPQNILVTSSGQIK 228 Lys2 13.6 CDK7 UniRef100_P50613 DLKPNNLLLDENGVLK 229 Lys2 −7.3 CDK9 UniRef100_P50750 DMKAANVLITR 230 Lys2 −13.1 CHK1 UniRef100_B4DT73 DIKPENLLLDER 231 Lys2 12.2 CHK2 UniRef100_O96017 DLKPENVLLSSQEEDCLIK 232 Lys2 −1.6 CK1a UniRef100_P48729 DIKPDNFLMGIGR 233 Lys2 −19.6 CK1d, UniRef100_P49674, DVKPDNFLMGLGKK 234 Lys2 −9.3 CK1e UniRef100_P48730 CK1g1, UniRef100_Q9Y6M4, KIGCGNFGELR 235 ATP Loop 1.3 CK1g2, UniRef100_P78368, CK1g3 UniRef100_Q9HCP0 CK1g2 UniRef100_P78368 DVKPENFLVGRPGTK 236 Lys2 −23.3 CLK2 UniRef100_P49760 LTHTDLKPENILFVNSDYEL 237 Lys2 −30.3 TYNLEK CLK3 UniRef100_P49761 YEIVGNLGEGTFGKVVECL 238 ATP Loop −4.0 DHAR CSK UniRef100_P41240 VSDFGLTKEASSTQDTGKL 239 Activation Loop 20.0 PVK DGKA UniRef100_P23743 IDPVPNTHPLLVFVNPKSG 240 ATP −16.3 GK DGKH UniRef100_Q86XP1 ATFSFCVSPLLVFVNSKSG 241 ATP 32.6 DNQGVK DGKQ UniRef100_P52824 GRLLTALVLPDLLHAKLPP 242 ATP −23.2 DSCPLLVFVNPKSGGLK DNAPK UniRef100_P78527 KGGSWIQEINVAEK 243 ATP −35.9 DNAPK UniRef100_P78527 EHPFLVKGGEDLR 244 ATP −63.7 eEF2K UniRef100_O00418 YIKYNSNSGFVR 245 ATP −22.0 Erk1 UniRef100_P27361 DLKPSNLLINTTCDLK 246 Lys2 −16.3 Erk2 UniRef100_P28482 DLKPSNLLLNTTCDLK 247 Lys2 −2.7 Erk3 UniRef100_Q16659 DLKPANLFINTEDLVLK 248 Lys2 31.8 Erk5 UniRef100_Q13164 DLKPSNLLVNENCELK 249 Lys2 −42.7 FER UniRef100_P16591 TSVAVKTCKEDLPQELK 250 Lys1 74.0 FES UniRef100_P07332 LRADNTLVAVKSCR 251 Lys1 36.1 FGR UniRef100_P09769 LIKDDEYNPCQGSKFPIK 252 Activation 70.3 Loop FRAP UniRef100_P42345 IQSIAPSLQVITSKQRPR 253 ATP −3.3 FRK UniRef100_P42685 HEIKLPVK 254 Activation 98.0 Loop FYN, SRC, UniRef100_P12931, QGAKFPIKWTAPEAALYGR 255 Activation 88.2 YES UniRef100_P07947, Loop UniRef100_P06241 GCK UniRef100_Q12851 DIKGANLLLTLQGDVK 256 Lys2 96.3 GCN2 UniRef100_Q9P2K8 DLKPVNIFLDSDDHVK 257 Lys2 5.4 GPRK6 UniRef100_P43250 DLKPENILLDDHGHIR 258 Lys2 −1.9 GSK3A UniRef100_P49840 DIKPQNLLVDPDTAVLK 259 Lys2 25.5 GSK3B UniRef100_P49841 DIKPQNLLLDPDTAVLK 260 Lys2 −3.5 HPK1 UniRef100_Q92918 DIKGANILINDAGEVR 261 Lys2 88.2 IKKa UniRef100_O15111 DLKPENIVLQDVGGK 262 Lys2 −3.1 IKKb UniRef100_O14920 DLKPENIVLQQGEQR 263 Lys2 −12.2 IKKe UniRef100_Q14164 SGELVAVKVFNTTSYLRPR 264 Lys1 −3.9 ILK UniRef100_Q13418 WQGNDIVVKVLK 265 Lys1 −0.4 ILK UniRef100_Q13418 ISMADVKFSFQCPGR 266 Protein 6.8 Kinase Domain IRAK1 UniRef100_P51617 AIQFLHQDSPSLIHGDIKSS 267 Lys2 7.6 NVLLDER IRAK3 UniRef100_Q9Y616 VEIQNLTYAVKLFK 268 Lys1 −7.1 IRAK4 UniRef100_Q9NWZ3 DIKSANILLDEAFTAK 269 Lys2 6.3 IRE1 UniRef100_O75460 DLKPHNILISMPNAHGK 270 Lys2 −0.6 ITPK1 UniRef100_Q13572 ESIFFNSHNVSKPESSSVLT 271 ATP −16.2 ELDKIEGVFERPSDEVIR JAK1 UniRef100_P23458 QLASALSYLEDKDLVHGN 272 Protein 9.0 domain1 VCTKNLLLAR Kinase Domain JAK1 UniRef100_P23458 IGDFGLTKAIETDKEYYTVK 273 Activation 29.3 domain2 Loop JAK1 UniRef100_P23458 YDPEGDNTGEQVAVKSLK 274 Lys1 24.0 domain2 PESGGNHIADLKK JAK3 UniRef100_P52333 IADFGLAKLLPLDKDYYVVR 275 Activation −4.3 domain2 Loop JNK1, UniRef100_P45983, DLKPSNIVVK 276 Lys2 31.5 JNK2, UniRef100_P53779, JNK3 UniRef100_P45984 KHS1 UniRef100_Q9Y4K4 NVHTGELAAVKIIK 277 Lys1 33.9 KHS2 UniRef100_Q8IVH8 NVNTGELAAIKVIK 278 Lys1 3.8 KSR1 UniRef100_Q8IVT5 SKNVFYDNGKVVITDFGLF 279 Activation −0.2 GISGVVR Loop KSR1, UniRef100_Q6VAB6, SKNVFYDNGK 280 Activation 1.4 KSR2 UniRef100_Q8IVT5 Loop LATS1 UniRef100_O95835 ALYATKTLR 281 Lys1 15.8 LATS2 UniRef100_Q9NRM7 DIKPDNILIDLDGHIK 282 Lys2 0.8 LCK UniRef100_P06239 EGAKFPIKWTAPEAINYGT 283 Activation 83.8 FTIK Loop LKB1 UniRef100_Q15831 DIKPGNLLLTTGGTLK 284 Lys2 3.6 LOK UniRef100_O94804 DLKAGNVLMTLEGDIR 285 Lys2 28.8 LRRK2 UniRef100_Q5S007 DLKPHNVLLFTLYPNAAIIAK 286 Lys2 −11.8 LYN UniRef100_P07948 VAVKTLKPGTMSVQAFLE 287 Lys1 85.7 EANLMK MAP2K1 UniRef100_Q02750 IMHRDVKPSNILVNSR 288 Lys2 6.6 MAP2K1, UniRef100_P36507, KLIHLEIKPAIR 289 Lys1 9.4 MAP2K2 UniRef100_Q02750 MAP2K1, UniRef100_P36507, DVKPSNILVNSR 290 Lys2 2.2 MAP2K2 UniRef100_Q02750 MAP2K2 UniRef100_P36507 HQIMHRDVKPSNILVNSR 291 Lys2 3.9 MAP2K3 UniRef100_P46734 DVKPSNVLINK 292 Lys2 −1.0 MAP2K4 UniRef100_P45985 DIKPSNILLDR 293 Lys2 0.4 MAP2K5 UniRef100_Q13163 DVKPSNMLVNTR 294 Lys2 −46.0 MAP2K6 UniRef100_P52564 DVKPSNVUNALGQVK 295 Lys2 2.0 MAP2K7 UniRef100_O14733 DVKPSNILLDER 296 Lys2 19.3 MAP3K1 UniRef100_Q13233 DVKGANLLIDSTGQR 297 Lys2 27.5 MAP3K2 UniRef100_Q9Y2U5 ELAVKQVQFDPDSPETSK 298 Lys1 −1.1 EVNALECEIQLLK MAP3K2, UniRef100_Q9Y2U5, DIKGANILR 299 Lys2 8.4 MAP3K3 UniRef100_Q99759 MAP3K3 UniRef100_Q99759 ELASKQVQFDPDSPETSKE 300 Lys1 10.0 VSALECEIQLLK MAP3K4 UniRef100_Q9Y6R4 DIKGANIFLTSSGLIK 301 Lys2 17.3 MAP3K5 UniRef100_Q99683 DIKGDNVLINTYSGVLK 302 Lys2 −10.2 MAP3K6 UniRef100_O95382 DIKGDNVLINTFSGLLK 303 Lys2 2.1 MARK2, UniRef100_P27448, DLKAENLLLDADMNIK 304 Lys2 −15.6 MARK3 UniRef100_Q7KZI7 MARK3 UniRef100_P27448 EVAIKIIDKTQLNPTSLQK 305 Lys1 2.6 MARK3, UniRef100_Q96L34, EVAIKIIDK 306 Lys1 −7.5 MARK4 UniRef100_P27448 MARK4 UniRef100_Q96L34 DLKAENLLLDAEANIK 307 Lys2 −28.5 MAST1, UniRef100_Q6P0Q8, DLKPDNLUTSMGHIK 308 Lys2 −24.8 MAST2 UniRef100_Q9Y2H9 MAST3 UniRef100_O60307 DLKPDNLLITSLGHIK 309 Lys2 −4.7 MASTL UniRef100_Q96GX5 GAFGKVYLGQK 310 ATP Loop 1.1 MASTL UniRef100_Q96GX5 LYAVKVVK 311 Lys1 −7.6 MELK UniRef100_Q14680 DLKPENLLFDEYHK 312 Lys2 −3.0 MER, UniRef100_Q06418, KIYSGDYYR 313 Activation 21.2 TYRO3 UniRef100_Q12866 Loop MET UniRef100_P08581 DMYDKEYYSVHNK 314 Activation 5.7 Loop MLK3 UniRef100_Q16584 DLKSNNILLLQPIESDDME 315 Lys2 −0.2 HK MLK4 UniRef100_Q5TCX8 DLKSSNILLLEK 316 Lys2 1.5 MLKL UniRef100_Q8NB16 APVAIKVFK 317 Lys1 −5.5 MPSK1 UniRef100_O75716 DLKPTNILLGDEGQPVLM 318 Lys2 −2.3 DLGSMNQACIHVEGSR MSK1 UniRef100_O75582 DIKLENILLDSNGHVVLTD 319 Lys2 −21.5 domain1 FGLSK MSK2 UniRef100_O75676 DLKLENVLLDSEGHIVLTD 320 Lys2 −8.1 domain1 FGLSK MST1 UniRef100_Q13043 ETGQIVAIKQVPVESDLQE 321 Lys1 7.5 IIK MST2 UniRef100_Q13188 ESGQVVAIKQVPVESDLQ 322 Lys1 8.6 EIIK MST3 UniRef100_Q9Y6E0 DIKAANVLLSEHGEVK 323 Lys2 −8.9 MST4 UniRef100_Q9P289 TQQVVAIKIIDLEEAEDEIE 324 Lys1 −37.3 DIQQEITVLSQCDSSYVTK MST4, UniRef100_O00506, DIKAANVLLSEQGDVK 325 Lys2 −2.4 YSK1 UniRef100_Q9P289 MYO3A, UniRef100_Q8NEV4, DVKGNNILLTTEGGVK 326 Lys2 22.9 MYO3B UniRef100_Q8WXR4 NDR1 UniRef100_Q15208 DIKPDNLLLDSK 327 Lys2 2.3 NDR2 UniRef100_Q9Y2H1 DIKPDNLLLDAK 328 Lys2 9.8 NEK1 UniRef100_Q96PY6 DIKSQNIFLTK 329 Lys2 −7.1 NEK2 UniRef100_P51955 DLKPANVFLDGK 330 Lys2 12.5 NEK3 UniRef100_P51956 SKNIFLTQNGK 331 Activation −8.6 Loop NEK4 UniRef100_P51957 DLKTQNVFLTR 332 Lys2 2.8 NEK6, UniRef100_Q8TDX7, DIKPANVFITATGVVK 333 Lys2 −1.8 NEK7 UniRef100_Q9HC98 NEK7 UniRef100_Q8TDX7 AACLLDGVPVALKK 334 Lys1 2.7 NEK8 UniRef100_Q86SG6 DLKTQNILLDK 335 Lys2 −7.8 NEK9 UniRef100_Q8TD19 DIKTLNIFLTK 336 Lys2 −10.7 NLK UniRef100_Q9UBE8 DIKPGNLLVNSNCVLK 337 Lys2 22.3 OSR1 UniRef100_C9JIG9, DVKAGNILLGEDGSVQIA 338 Lys2 32.2 UniRef100_O95747 DFGVSAFLATGGDITR p38a UniRef100_Q16539 DLKPSNLAVNEDCELK 339 Lys2 76.1 p38a UniRef100_Q16539 QELNKTIWEVPER 340 Protein 88.4 Kinase Domain p38d, UniRef100_O15264, DLKPGNLAVNEDCELK 341 Lys2 51.5 p38g UniRef100_P53778 p70S6K UniRef100_P23443 DLKPENIMLNHQGHVK 342 Lys2 −74.1 p70S6Kb UniRef100_Q9UBS0 DLKPENIMLSSQGHIK 343 Lys2 3.5 PAN3 UniRef100_Q58A45 VMDPTKILITGK 344 ATP 7.3 PCTAIRE1 UniRef100_Q00536 SKLTDNLVALKEIR 345 Lys1 53.3 PCTAIRE2, UniRef100_Q00537, SKLTENLVALKEIR 346 Lys1 72.9 PCTAIRE3 UniRef100_Q07002 PDHK1 UniRef100_Q15118 SPGQPIQVVYVPSHLYHM 347 ATP −23.7 VFELFKNAMR PEK UniRef100_Q9NZJ5 DLKPSNIFFTMDDVVK 348 Lys2 −21.9 PFTAIRE1 UniRef100_O94921 LVALKVIR 349 Lys1 64.0 PHKg1 UniRef100_Q16816 DLKPENILLDDNMNIK 350 Protein −0.9 Kinase Domain PHKg2 UniRef100_P15735 ATGHEFAVKIMEVTAER 351 Lys1 7.1 PI4K2B UniRef100_Q8TCG2 SEEPYGQLNPKWTK 352 ATP 33.4 PI4KA, UniRef100_A4QPH2, SGTPMQSAAKAPYLAK 353 ATP 2.1 PI4KAP2 UniRef100_P42356 PI4KB UniRef100_Q9UBF8 VPHTQAVVLNSKDK 354 ATP 23.7 PIK3C2B UniRef100_O00750 VIFKCGDDLRQDMLTLQ 355 ATP −15.7 MIR PIK3C3 UniRef100_Q8NEB9 TEDGGKYPVIFKHGDDLR 356 ATP −29.7 PIK3CB UniRef100_P42338 VFGEDSVGVIFKNGDDLR 357 ATP −3.9 QDMLTLQMLR PIK3CD UniRef100_O00329 VNWLAHNVSKDNRQ 358 ATP −22.8 PIK3CG UniRef100_P48736 KKPLWLEFK 359 ATP −20.1 PIP4K2A UniRef100_P48426 AKELPTLKDNDFINEGQK 360 ATP −19.5 PIP4K2C UniRef100_Q8TBX8 TLVIKEVSSEDIADMHSNL 361 ATP −7.3 SNYHQYIVK PIP5K3 UniRef100_Q9Y2I7 GGKSGAAFYATEDDRFILK 362 ATP 21.7 PITSLRE UniRef100_P21127 DLKTSNLLLSHAGILK 363 Lys2 10.2 PKCa, UniRef100_P05771, DLKLDNVMLDSEGHIK 364 Lys2 −86.4 PKCb UniRef100_P17252 PKCe UniRef100_Q02156 DLKLDNILLDAEGHCK 365 Lys2 27.7 PKCi UniRef100_P41743 IYAMKVVK 366 Lys1 −54.3 PKD2 UniRef100_Q9BZL6 DVAVKVIDK 367 Lys1 −5.4 PKN1 UniRef100_Q16512 VLLSEFRPSGELFAIKALK 368 Lys1 1.8 PKR UniRef100_P19525 DLKPSNIFLVDTK 369 Lys2 −1.7 PLK1 UniRef100_P53350 CFEISDADTKEVFAGKIVPK 370 Lys1 18.8 PLK4 UniRef100_O00444 AESIHTGLEVAIKMIDKK 371 Lys1 −17.3 PRP4 UniRef100_Q13523 CNILHADIKPDNILVNESK 372 Lys2 −5.5 PRPK UniRef100_Q96S44 FLSGLELVKQGAEAR 373 ATP Loop −16.0 PYK2 UniRef100_Q14289 YIEDEDYYKASVTR 374 Activation 30.5 Loop RIPK1 UniRef100_Q13546 DLKPENILVDNDFHIK 375 Lys2 23.1 RIPK3 UniRef100_Q9Y572 DLKPSNVLLDPELHVK 376 Lys2 70.2 ROCK1, UniRef100_O75116, DVKPDNMLLDK 377 Lys2 −0.2 ROCK2 UniRef100_Q13464 RSK1 UniRef100_Q15418 DLKPENILLDEEGHIKLTDF 378 Lys2 −29.6 domain1 GLSKEAIDHEK RSK1 UniRef100_P51812, DLKPENILLDEEGHIK 379 Lys2 −25.1 domain1, UniRef100_Q15418, RSK2 UniRef100_Q15349 domain1, RSK3 domain1 RSK1 UniRef100_Q15418 DLKPSNILYVDESGNPECLR 380 Lys2 1.0 domain2 RSK2 UniRef100_P51812 DLKPENILLDEEGHIKLTDF 381 Lys2 −36.7 domain1 GLSKESIDHEK RSK2 UniRef100_P51812 DLKPSNILYVDESGNPESIR 382 Lys2 2.8 domain2 RSK3 UniRef100_Q15349 DLKPENILLDEEGHIKITDF 383 Lys2 −37.8 domain1 GLSK RSKL1 UniRef100_Q96S38 VLGVIDKVLLVMDTR 384 ATP 21.8 SGK3 UniRef100_Q96BR1 FYAVKVLQK 385 Lys1 16.6 SLK UniRef100_Q9H2G2 DLKAGNILFTLDGDIK 386 Lys2 13.8 SMG1 UniRef100_Q96Q15 DTVTIHSVGGTITILPTKTK 387 ATP −3.6 PK SNRK UniRef100_Q9NRH2 DLKPENVVFFEK 388 Lys2 24.5 SRC UniRef100_P12931 VAIKTLKPGTMSPEAFLQE 389 Lys1 82.7 AQVMKK SRPK1 UniRef100_Q96SB4 IIHTDIKPENILLSVNEQYIR 390 Lys2 −9.1 SRPK1, UniRef100_P78362, FVAMKVVK 391 Lys1 −38.7 SRPK2 UniRef100_Q96SB4 STK33 UniRef100_Q9BYT3 DLKLENIMVK 392 Lys2 −8.0 STLK5 UniRef100_Q7RTN6 YSVKVLPWLSPEVLQQNL 393 Activation Loop 12.0 QGYDAK SYK UniRef100_P43405 ISDFGLSKALR 394 Activation 6.6 Loop TAK1 UniRef100_O43318 DLKPPNLLLVAGGTVLK 395 Lys2 0.4 TAO1, UniRef100_Q7L7X3, DIKAGNILLTEPGQVK 396 Lys2 87.1 TAO3 UniRef100_Q9H2K8 TAO2 UniRef100_Q9UL54 DVKAGNILLSEPGLVK 397 Lys2 92.0 TBK1 UniRef100_Q9UHD2 TGDLFAIKVFNNISFLRPV 398 Lys1 −18.0 DVQMR TEC UniRef100_P42680 YVLDDQYTSSSGAKFPVK 399 Activation 20.6 Loop TLK1 UniRef100_Q9UKI8 YLNEIKPPIIHYDLKPGNILL 400 Lys2 11.5 VDGTACGEIK TLK2 UniRef100_Q86UE8 YLNEIKPPIIHYDLKPGNILL 401 Lys2 10.2 VNGTACGEIK ULK1 UniRef100_O75385 DLKPQNILLSNPAGR 402 Lys2 8.8 ULK3 UniRef100_D3DW67 NISHLDLKPQNILLSSLEKP 403 Lys2 27.1 HLK VRK2 UniRef100_Q86Y07 MLDVLEYIHENEYVHGDIK 404 Lys2 −1.2 AANLLLGYK Wnk1, UniRef100_Q9Y3S1, GSFKTVYK 405 ATP Loop 11.2 Wnk2 UniRef100_D3DUP1 Wnk1, UniRef100_Q9Y3S1, DLKCDNIFITGPTGSVK 406 Lys2 −1.1 Wnk2, UniRef100_D3DUP1, Wnk3 UniRef100_Q9BYP7 YANK3 UniRef100_Q86UX6 DVKPDNILLDER 407 Lys2 −43.1 ZAK UniRef100_Q9NYL2 WISQDKEVAVKK 408 Lys1 75.8 ZAP70 UniRef100_P43403 ISDFGLSKALGADDSYYTAR 409 Activation 10.7 Loop ZC1/HGK, UniRef100_O95819, DIKGQNVLLTENAEVK 410 Lys2 57.5 ZC2/TNIK, UniRef100_Q9UKE5, ZC3/MINK UniRef100_Q8N4C8 ZC2/TNIK UniRef100_Q9UKE5 TGQLAAIKVMDVTGDEEE 411 Lys1 46.0 EIKQEINMLKK

Example 3 p-BTK and p-Hck Inhibition Protocol for PhosFlow Studies

PhosFlow was performed to detect levels of phosphorylation for BTK-pY223 (BD Biosciences) and Hck-pY410 (Abcam) in BCWM.1 cells, in BCWM cells that stably overexpress HCK (BCWM.1_HCK-wt) and in BCWM.1 cells that stably overexpress the T338M mutant of HCK (BCWM.1_HCK-mu). Cells were fixed with BD Phosflow Fix Buffer I (BD Biosciences) at 37° C. for 10 min, then washed twice with BD Phosflow Perm/Wash Buffer I (BD Biosciences). Cells were suspended in BD Phosflow Perm/Wash Buffer I at 10 million/ml and antibodies aliquoted to flow tubes with 100 μl cells. Cells were incubated at room temperature for 30 min in the dark. Cells were washed twice with BD Phosflow Perm/Wash Buffer I before performing flow analysis using a BD™ FACSCanto II flow cytometer.

Protocol for Apoptosis Analysis

Apoptosis analysis of WM patient primary lymphoplasmacytic cells (LPCs) was preformed following A-5 and A-14 treatment of Bone marrow mononuclear cells (BMMC) from WM patients for 24 hours. Apoptosis analysis was performed using Annexin V/Propidium iodide staining with the Apoptosis Detection Kit I (BD Pharmingen) in CD19-APC-cy7 antibody (BD Pharmingen) gated LPCs population.

Results

PhosFlow studies indicate both A-5 and A-14 inhibit Hck and BTK phosphorylation in BCWM.1 cells and BCWM.1 cells with genetic engineered expression of Hck wild type (-wt) and T338M gatekeeper mutant (-mu) with both 0.5 μM and 0.1 μM doses (shown by Table 6 and Table 7, respectively). In addition, the expression of Hck-wt or Hck-mu increased the resistance to the inhibition of both Hck and BTK phosphorylations by A-5 and A-14, with more resistance presented in Hck-mu expressing BCWM.1 cells. Both A-5 and A-14 induced significant apoptosis in WM patient primary LPCs compared with DMSO control, as shown in Table 8.

TABLE 6 Relative p-BTK p-Hck MFI % _Hck- _Hck- _Hck- _Hck- (0.5 μM BCWM.1 BCWM.1 wt BCWM.1 mu BCWM.1 BCWM.1 wt BCWM.1 mu drugs) 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min DMSO 100 100 100 100 100 100 100 100 100 100 100 100 A-5 56.3 42.3 73.6 69.9 100.7 90.4 68.2 49 80.4 77.7 102.2 81.1 A-14 51.5 27.4 65.6 29.7 112.1 83.9 59.3 35.6 68.6 41.5 89.7 52.3

TABLE 7 Relative p-BTK p-Hck MFI % _Hck- _Hck- _Hck- _Hck- (0.1 μM BCWM.1 BCWM.1 wt BCWM.1 mu BCWM.1 BCWM.1 wt BCWM.1 mu drugs) 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min DMSO 100 100 100 100 100 100 100 100 100 100 100 100 A-5 68.1 52.7 82.1 78.3 70.9 70.4 76.3 50.5 76 80.6 95.3 69.6 A-14 81.8 50.1 76.3 72 75.3 61.2 73.6 57.8 75.8 78.9 83.1 63.7

TABLE 8 Dose (1.0 μM) Dose (0.5 μM) Dose (0.2 μM) Apoptosis Apoptosis Relative Apoptosis Apoptosis Relative Apoptosis Apoptosis Relative Treatments (%) to DMSO (%) to DMSO (%) to DMSO Patient 1 Untreated 40.9 114.30% DMSO 39.2   100% A-5 57.7 147.20% Patient 2 N 14.2  97.30% DMSO 14.6   100% A-5 28.9 197.90% Patient 3 N 14.529  95.49% DMSO 15.216 100.00% A-5 29.48 193.70% Patient 4 N 29.83 103.00% DMSO 29.75 100.00% A-5 48.56 163.20% Patient 5 N 18.69 110.70% DMSO 16.89   100% A-5 30.5 180.60% 23.25 137.70% A-14 46.86 277.40% 39.24 232.30% Patient 6 N 8.66 117.50% DMSO 7.37   100% A-5 17.82 241.80% A-14 20.88 283.30% Patient 7 DMSO 6.46 100.00% A-5 18.2 281.70% 17.23 266.70% A-14 31.51 487.80% 22.62 350.20% Patient 8 DMSO 5.38 100.00% A-5 17.31 321.75% 11.04 205.20% A-14 31.58 586.99% 12.9 239.78% Patient 9 DMSO 7.6 100.00% A-14 43.7 575.00% 24.8 326.32% Patient N 17.6 113.50% 10 DMSO 15.5   100% A-5 28.7 185.20% 21.5 138.70% A-14 52 335.50% 27.9 180.00% Patient N 26.2 112.70% 11 DMSO 25.5   100% A-5 47 184.30% 30.2 118.40% A-14 71.8 281.60% 53.1 208.20%

Equivalents and Scope

In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above

Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims. 

1. A compound of Formula (A):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; wherein: each instance of R^(A) is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, —OR^(A1), —N(R^(A1))₂, —CN, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —NO₂, —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1), —NR^(A1)S(═O)₂R^(A1), —S(═O)₂R^(A1), or —S(═O)₂N(R^(A1))₂; each instance of R^(B) is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A1))₂, —CN, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —NO₂, —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1), —NR^(A1)S(═O)₂R^(A1), —S(═O)₂R^(A1), or —S(═O)₂N(R^(A1))₂; each instance of R^(A1) is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R^(A1) groups are joined to form an optionally substituted heterocyclic ring; one instance of A that is included in Ring B is CR^(Y); the other instance of A that is included in Ring B is CR^(Y) or N; each instance of R^(Y) is independently H, halogen, or substituted or unsubstituted C₁₋₆ alkyl; each instance of R^(X) is independently selected from the group consisting of R^(D), optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and —N(R^(A1))(R^(Xa)); each instance of R^(Xa) is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —S(═O)R^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1), —S(═O)₂N(R^(A1))₂, —N(R^(A1))₂, and a nitrogen protecting group; k is 0, 1, 2, 3, or 4; l is 1, 2, 3, 4, or 5; Q and U are taken together to be —NR^(A)(C═O)— or —(C═O)NR^(A)—; and R^(D) is an electrophilic moiety of any one of Formulae (i-1)-(i-18):

R^(D1) is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^(D1a), —N(R^(D1a))₂, —SR^(D1a), —CH₂OR^(D1a), —CH₂N(R^(D1a))₂, —CH₂SR^(D1a), —C(═O)R^(D1a), —C(═O)OR^(D1a), —C(═O)SR^(D1a), —C(═O)N(R^(D1a))₂, —C(═S)R^(D1a), —C(═S)OR^(D1a), —C(═S)SR^(D1a), —C(═S)N(R^(D1a))₂, —C(═NR^(D1a))R^(D1a), —C(═NR^(D1a))OR^(D1a), —C(═NR^(D1a))SR^(D1a), and —C(═NR^(D1a))N(R^(D1a))₂, wherein each occurrence of R^(D1a) is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^(D1a) groups are joined to form an optionally substituted heterocyclic ring; R^(D2) is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^(D2a), —N(R^(D2a))₂, —SR^(D2a), —CH₂OR^(D2a), —CH₂N(R^(D2a))₂, —CH₂SR^(D2a), —C(═O)R^(D2a), —C(═O)OR^(D2a), —C(═O)SR^(D2a), —C(═O)N(R^(D2a))₂, —C(═S)R^(D2a), —C(═S)OR^(D2a), —C(═S)SR^(D2a), —C(═S)N(R^(D2a))₂, —C(═NR^(D2a))R^(D2a), —C(═NR^(D2a))OR^(D2a), —C(═NR^(D2a))SR^(D2a), and —C(═NR^(D2a))N(R^(D2a))₂, wherein each occurrence of R^(D2a) is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^(D2a) groups are joined to form an optionally substituted heterocyclic ring; R^(D3) is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^(D3a), —N(R^(D3a))₂, —SR^(D3a), —CH₂OR^(D3a), —CH₂N(R^(D3a))₂, —CH₂SR^(D3a), —C(═O)R^(D3a), —C(═O)OR^(D3a), —C(═O)SR^(D3a), —C(═O)N(R^(D3a))₂, —C(═S)R^(D3a), —C(═S)OR^(D3a), —C(═S)SR^(D3a), —C(═S)N(R^(D3a))₂, —C(═NR^(D3a))R^(D3a), —C(═NR^(D3a))OR^(D3a), —C(═NR^(D3a))SR^(D3a), and —C(═NR^(D3a))N(R^(D3a))₂, wherein each occurrence of R^(D3a) is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^(D3a) groups are joined to form an optionally substituted heterocyclic ring; optionally R^(D1) and R^(D3), or R^(D2) and R^(D3), or R^(D1) and R^(D2) are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; R^(D4) is a leaving group; R^(D5) is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group; Y^(Z) is —O—, —S—, or —NR^(D6)—, wherein R^(D6) is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group; a is 1 or 2; z is 0, 1, 2, 3, 4, 5, or 6; and optionally R^(D5) and one R^(C) are joined to form an optionally substituted heterocyclic ring.
 2. The compound of claim 1, wherein Q and U are taken together to be


3. The compound of claim 1, wherein the compound is of Formula (A1):

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim 3, wherein the compound is of Formula (A1-a), (A1-b), (A1-c), or (A1-d):

or a pharmaceutically acceptable salt thereof, wherein: each instance of R^(Xc) is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —CN, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —NO₂, —N₃, —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1), —NR^(A1)C(═O)N(R^(A1))₂, —NR^(A1)S(═O)₂R^(A1), —NR^(A1)S(═O)R^(A1), —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —S(═O)R^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), and —S(═O)₂N(R^(A1))₂. 5-7. (canceled)
 8. The compound of claim 1, wherein the compound is of Formula (A2):

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim 8, wherein the compound is of Formula (A2-a), (A2-b), (A2-c), or (A2-d):

or a pharmaceutically acceptable salt thereof, wherein: each instance of R^(Xc) is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —CN, —C(═O)R^(A1), —C(═O)OR^(A1), —C(═O)N(R^(A1))₂, —NO₂, —N₃, —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1), —NR^(A1)C(═O)N(R^(A1))₂, —NR^(A1)S(═O)₂R^(A1), —NR^(A1)S(═O)R^(A1), —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)N(R^(A1))₂, —S(═O)R^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), and —S(═O)₂N(R^(A1))₂. 10-12. (canceled)
 13. The compound of claim 1, wherein the compound is of Formula (A3):

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim 1, wherein the compound is of Formula (A4):

or a pharmaceutically acceptable salt thereof.
 15. (canceled)
 16. The compound of claim 13, wherein R^(D) is selected from the group consisting of:

wherein, R^(D2) is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^(D2a), —N(R^(D2a))₂, —SR^(D2a), —CH₂OR^(D2a), —CH₂N(R^(D2a))₂, —CH₂SR^(D2a), —C(═O)R^(D2a), —C(═O)OR^(D2a), —C(═O)SR^(D2a), —C(═O)N(R^(D2a))₂, —C(═S)R^(D2a), —C(═S)OR^(D2a), —C(═S)SR^(D2a), —C(═S)N(R^(D2a))₂, —C(═NR^(D2a))R^(D2a), —C(═NR^(D2a))OR^(D2a), —C(═NR^(D2a))SR^(D2a), and —C(═NR^(D2a))N(R^(D2a))₂, wherein each occurrence of R^(D2a) is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^(D2a) groups are joined to form an optionally substituted heterocyclic ring; R^(D3) is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^(D3a), —N(R^(D3a))₂, —SR^(D3a), —CH₂OR^(D3a), —CH₂N(R^(D3a))₂, —CH₂SR^(D3a), —C(═O)R^(D3a), —C(═O)OR^(D3a), —C(═O)SR^(D3a), —C(═O)N(R^(D3a))₂, —C(═S)R^(D3a), —C(═S)OR^(D3a), —C(═S)SR^(D3a), —C(═S)N(R^(D3a))₂, —C(═NR^(D3a))R^(D3a), —C(═NR^(D3a))OR^(D3a), —C(═NR^(D3a))SR^(D3a), and —C(═NR^(D3a))N(R^(D3a))₂, wherein each occurrence of R^(D3a) is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^(D3a) groups are joined to form an optionally substituted heterocyclic ring; and R^(D5) is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group.
 17. The compound of claim 1, wherein R^(A) is substituted or unsubstituted C₁₋₆ alkyl.
 18. (canceled)
 19. The compound of claim 1, wherein l is
 1. 20-23. (canceled)
 24. The compound of claim 1, wherein one R^(B) group is substituted or unsubstituted C₁₋₆alkyl. 25-26. (canceled)
 27. The compound of claim 1, wherein one R^(B) group is substituted or unsubstituted —CH₂-(piperazinyl).
 28. (canceled)
 29. The compound of claim 1, wherein, one R^(B) group is haloalkyl.
 30. (canceled)
 31. The compound of claim 1, wherein one R^(B) group is substituted or unsubstituted imidazoyl.
 32. (canceled)
 33. The compound of claim 1, wherein one R^(B) group is substituted or unsubstituted piperazinyl.
 34. (canceled)
 35. The compound of claim 1, wherein one R^(B) group is substituted or unsubstituted morpholine. 36-39. (canceled)
 40. A compound of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.
 41. A pharmaceutical composition comprising: a compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a compound of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and optionally a pharmaceutically acceptable excipient. 42-45. (canceled)
 46. A method of treating a B cell neoplasm in a subject comprising administering to the subject an effective amount of: a compound of claim 1, or a pharmaceutically acceptble salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a compound of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. 47-56. (canceled)
 57. A kit comprising: a container comprising: a compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a compound of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and instructions for use in a subject.
 58. (canceled) 